research topics in cancer metastasis

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Current challenges in metastasis research and future innovation for clinical translation

Amelia l. parker.

1 Matrix and Metastasis Lab, Kinghorn Cancer Centre, Garvin Institute of Medical Research, Darlinghurst, NSW 2010 Australia

2 St Vincent’s Clinical School, UNSW Sydney, Sydney, 2052 Australia

Madeleine Benguigui

3 Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 31096 Haifa, Israel

Jaime Fornetti

4 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake, UT USA

Erica Goddard

5 Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA USA

Serena Lucotti

6 Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine, NY New York, USA

Jacob Insua-Rodríguez

7 Department of Physiology and Biophysics, Department of Biological Chemistry, Chao Family Comprehensive Cancer Centre, University of California, Irvine, CA USA

Adrian P. Wiegmans

8 Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, Queensland University of Technology (QUT), Translational Research Institute, Woolloongabba, QLD 4121 Australia

Early Career Leadership Council of the Metastasis Research Society

Associated data.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

While immense strides have been made in understanding tumor biology and in developing effective treatments that have substantially improved the prognosis of cancer patients, metastasis remains the major cause of cancer-related death. Improvements in the detection and treatment of primary tumors are contributing to a growing, detailed understanding of the dynamics of metastatic progression. Yet challenges remain in detecting metastatic dissemination prior to the establishment of overt metastases and in predicting which patients are at the highest risk of developing metastatic disease. Further improvements in understanding the mechanisms governing metastasis have great potential to inform the adaptation of existing therapies and the development of novel approaches to more effectively control metastatic disease. This article presents a forward-looking perspective on the challenges that remain in the treatment of metastasis, and the exciting emerging approaches that promise to transform the treatment of metastasis in cancer patients.

Introduction

Advances in understanding the key features of primary tumors have relied on innovation across specialized fields, culminating in improved clinical staging and patient survival rates. These advances have also enhanced our understanding of secondary tumor formation, or metastasis, that remains the major cause of cancer-related deaths. Metastasis is defined as the process in which cancer spreads from the primary tumor and establishes at anatomically distinct sites. While tremendous technology-driven advances in our understanding of the metastatic process are revealing promising targetable mechanisms, improving the outcomes of patients with metastatic disease remains a significant challenge. In this perspectives article we identify opportunities for emerging fields of investigation that have the potential to fundamentally revolutionize not only our understanding of the metastatic process, but also the way in which metastasis is treated.

Despite advances in cancer detection and treatment, residual disseminated disease remains present but undetected in a considerable proportion of patients whose primary tumor has been successfully treated. This residual disease can be present as micrometastases, defined as multicellular secondary tumor cell clusters, or as disseminated single tumor cells (DTCs) that are currently too small to detect in clinical diagnostic scans and persist as potential sources of subsequent metastatic relapse [ 1 ]. The latency period between initial diagnosis and metastatic recurrence varies between months and years and a number of models have been proposed to explain these dynamics. One predominant model is that disseminated cells undergo a period of cellular dormancy prior to awakening and giving rise to overt metastases [ 2 , 3 ]. Alternative models propose that the growth rate of disseminated cells remains relatively constant and instead it is the balance between proliferation and cell death in the disseminated cells that constrains the emergence of overt metastases until proliferation rates dominate [ 4 ]. The maturation models suggests that disseminated tumour cells must first acquire further genomic alterations that enable their overt growth at secondary sites, and this maturation process results in delayed formation of detectable secondary tumors following dissemination [ 4 ]. It is likely that latency periods and the evolution of metastatic disease results from mixtures of these models, and that the contribution of each model to patient outcome differs between tumour types, secondary sites and is influenced by multiple host factors. Highly variable latency periods present a challenge in monitoring patients for metastatic emergence. Furthermore, current diagnostic approaches lack the sensitivity to detect this minimal residual disease, and as a result, the temporal dynamics of tumor cell dissemination and the overall burden of disseminated disease remains unclear for most cancer types. Yet, while the presence of substantial micrometastatic disease is suggestive of a high risk of relapse, not all patients will develop overt metastases from these disseminated cells. Monitoring and modelling tumor latency dynamics, in particular dormancy and reawakening, using patient avatars is crucial for understanding relapse mechanisms and predicting patient populations at risk.

The processes that govern the dynamics of tumor cell dissemination from the primary site, seeding at secondary sites, and ultimately their outgrowth into overt metastases are emerging as complex, dynamic and spatially compartmentalized interactions between cancer cells and the local tissue microenvironment [ 5 – 7 ]. The additional impacts of host and environmental factors adds further complexity to the myriad regulators of tumor progression, confounding our ability to accurately predict the trajectory of each patient’s cancer and the most effective treatment. This intra- and inter-individual complexity heralds an era of precision medicine that exploits our understanding of these factors to tailor therapies that specifically target metastatic disease.

To achieve a precision medicine framework that improves the outcome of patients with metastatic disease, we must understand the collective influence of cancer cell intrinsic, tumor microenvironmental, host, and environmental factors on tumor behavior before translating this knowledge into targeted therapies. Growing evidence indicates that despite the unambivalent utility of chemotherapy in successfully treating the primary tumor and improving patient outcomes, it has been demonstrated that some chemotherapies and dosing regimes can accelerate metastatic progression in some in vivo models in a context-specific manner [ 8 , 9 ] and further study is required to determine if similar effects are seen in patients. Understanding how primary tumor treatments affect metastatic dissemination provides an opportunity to more effectively implement existing treatments to also inhibit metastasis, while also suggesting that novel therapeutic approaches may be required to specifically target metastasis. Precision medicine approaches that take into account the dynamics of metastatic latency, outgrowth and response to primary tumor therapies for those metastases that progress will revolutionize the clinical management and outcomes for cancer patients. As depicted in Fig.  1 , major challenges to realizing improved outcomes in metastatic disease can be summarized as:

Current challenges in the management of metastatic disease and areas of research addressing these challenges. Created with BioRender.com

• Detecting and quantifying the metastatic burden throughout treatment.
• Predicting which patients will develop overt metastatic disease.
• Understanding the mechanisms governing tumor metastasis.
• Developing more effective metastasis-targeted treatments.

Emerging advances overcoming these challenges have the potential to transform the clinical management of metastatic disease across cancer types (Fig.  2 ).

Emerging advances in metastasis research. Created with BioRender.com

Dynamically defining metastatic burden during treatment

Current approaches: improving pathological assessments.

In order to improve the management of metastatic disease, it is imperative to obtain an accurate picture of when metastatic dissemination occurs, and how this process defines the risk profile for individuals both at diagnosis and throughout treatment. While great gains have been made in mapping the dynamics of tumor progression in many cancer types, much work remains to create a comprehensive temporal map of metastatic progression for each tumor type. To date, advancements in accurately assessing disseminated tumor burden in patients have been hampered by the limited sensitivity of radiological diagnostic scans for micrometastatic disease. Lymph node assessment, including sentinel node mapping with pathological assessment and ultrastaging (e.g. cytokeratin staining) as a surrogate for metastatic dissemination, has instead been used as a mainstay of metastatic disease staging in surgically resected cancers [ 10 ]. However, the recent integration of deep learning image analysis algorithms, which use multiple tissue features to define the presence of cancer cells, into clinically-established pipelines are improving the sensitivity and reproducibility of pathological metastasis staging [ 11 , 12 ]. In particular, Convolutional Neural Networks (CNN) have been the most widely studied artificial intelligence (AI) architecture for segmenting pathological images to classify tumour-associated regions of interest [ 13 , 14 ]. While the large amount of data required to train CNN architectures remains a significant hurdle in developing robust algorithms, these network architectures have been used to develop the most advanced AI algorithms to improve pathological staging, such as those developed from the CAncer MEtastases in LYmph Nodes Challenge (CAMELYON) [ 15 ]. The best performing algorithms to come out of this challenge were able to diagnose positive lymph node metastases with improved accuracy and efficiently compared with a panel of 11 pathologists [ 16 ]. This has led to the next phase of challenges that test AI capability to identify metastatic tissue in histopathologic scans demonstrating a pooled sensitivity of 82%, specificity of 84% and AUC of 0.90 for identification of tumor metastasis based on a summary of 2620 studies [ 16 ]. As the morphological and biochemical characteristics of tissue sites primed for metastatic colonisation become more clearly defined, we propose that the capacity of AI to detect overt metastasis will soon transfer to the ability to detect these pre-metastatic niches with equivalent accuracy. Such improvements in current clinical diagnostic pipelines will enable the early detection of metastatic dissemination to accurately prioritize patients for the most effective treatment.

Despite these improvements, metastatic lymph node assessment, by its nature, only captures cells that are within the lymphatic system and fails to detect cancer cells that have already disseminated to distant organs. Therefore, there is a clear need to improve the sensitivity and specificity of current diagnostic scans and develop label-free technologies that together can provide a whole-body picture of micrometastatic burden to define prognosis. In this regard, cross-platform imaging technologies that extend existing radiographic and radiological imaging technology to detect micrometastatic sites are showing promise [ 17 ].

The next phase in developing AI and imaging technology is in the detection of sites primed for metastatic colonization, thereby enabling the earliest assessment of metastatic risk and the opportunity to prevent the establishment of micrometastatic disease. These sites, known as pre-metastatic niches, are regions within distant organs that, under the influence of primary tumor-derived systemic factors, are primed to support the establishment and persistence of metastatic disease [ 18 ]. These pre-metastatic niches have now been characterized in the lungs [ 19 – 21 ], liver [ 22 ], lymph nodes [ 23 ], bone marrow [ 24 ] and brain [ 19 ] in both pre-clinical models and cancer patients. While the specific features of these niches appear to be tumor- and organ-dependent, vascular leakiness, increased inflammation (e.g. TLR4 activation), alteration of the extracellular matrix (ECM), recruitment of immunosuppressive cells (including macrophages, bone marrow derived cells (BMDCs) and regulatory T cells) as well as the activation and metabolic reprogramming of resident stromal cells are all common features of the pre-metastatic niche [ 26 ]. Together, these changes shape the pre-metastatic niche to be more receptive of tumor cell settlement by enhancing nutrient availability, vessel permeability, inflammation and cancer cell migration, survival and adhesion to ECM components at these distant sites. Altered textural features in radiological scans of axillary lymph nodes and metastatic sites that reflect increased matrix deposition or tissue density for example [ 17 , 22 ], are showing promise in the detection of these pre-metastatic niches [ 25 ], as are emerging imaging agents targeted against specific features of the pre-metastatic niche, such as overexpression of the α4β1 integrin receptor [ 27 ] or the presence of specific fibronectin isoforms in the ECM [ 17 ]. For example, radiomic analysis of the liver parenchyma on presurgical CT scans has been shown to predict the future development of hepatic metastases in colon cancer patients following primary tumor resection [ 25 ].

Further progress developing these emerging technologies will facilitate the dynamic monitoring of metastatic dissemination, allowing for rapid adaptation of therapies to maximize clinical responses (Table  1 ).

Observational clinical trials to improve metastasis detection and understand risk associations

Monitoring metastatic spread during treatment response

Liquid biopsy biomarker detection is a promising complementary approach to image-based detection of metastatic disease. Liquid biopsies are derived from plasma, serum or urine, and their minimally invasive nature makes them amenable to longitudinal tracking of metastatic progression in response to therapy. Detecting circulating tumor cells (CTCs) or their DNA (circulating tumor DNA, ctDNA) in plasma and serum are currently regarded as the most direct methods for assessing disseminated tumor burden using liquid biopsies. The number of CTCs or amount of ctDNA detected after therapy are robust readouts for treatment efficacy and with their superior sensitivity, enable the detection of relapse many months earlier than current radiological imaging procedures allow [ 28 ].

Despite the promise of monitoring CTCs as a direct measure of tumor cell dissemination [ 29 ], clinical implementation of CTC biomarkers as decision-making tools has been hampered by the scarcity of CTCs in blood specimens, a lack of standardized cell isolation approaches and inadequate sensitivity. CELLSEARCH TM , currently the only FDA-approved molecular pathology assay to detect CTCs, has overcome sensitivity limitations by implementing an EpCAM-positivity CTC enrichment step followed by an imaging-based tumor cell detection using cytokeratin and nuclear staining [ 30 , 31 ]. Although EpCAM+ enrichment and cytokeratin staining is a standard approach in a research setting, growing evidence indicates that EpCAM enrichment likely captures a subset of epithelial tumor cells and may not capture those tumor cells that have undergone a mesenchymal transition during metastatic dissemination [ 31 ], thereby limiting the assay’s applicability to specific epithelial cancers. Such approaches to standardize the isolation and enrichment of CTCs will provide insight into the dynamics of tumor cell dissemination as well as the opportunity to identify pro-metastatic features of cancer cells that can be therapeutically targeted [ 32 , 33 ].

Comparatively, ctDNA biomarker development has leveraged the sequencing revolution to demonstrate superior sensitivity and specificity compared with CTC analysis [ 29 ]. CtDNA markers that show considerable promise for clinical translation are mapped to mutated DNA regions corresponding to prevalent cancer drivers and are therefore cancer-type specific. These include mutant adenomatous polyposis coli ( APC ), epidermal growth factor receptor ( EGFR ) and Kirsten rat sarcoma virus ( KRAS ) DNA in the plasma of colorectal cancer patients as indicators of response to conventional and EGFR-targeted therapies, respectively, which are being developed for clinical use [ 34 , 35 ]. More recently, digital drop PCR pre-amplification and fluorescent probes have been developed into a promising standardized assay that detects ctDNA derived from mutant histone H3-genes in pediatric diffuse midline glioma patients, a tumor type that is generally not surgically accessible [ 36 ]. While these highly specific single-gene approaches are valuable for monitoring targeted therapy response, a panel of multiple ctDNA gene targets will be required to capture the burden of DTCs derived from diverse tumor types and highly clonal, genetically heterogeneous tumors. Multi-gene profiling of ctDNA in plasma samples, such as that implemented by MSK-ACCESS (MSK-Analysis of Circulating Cell-free DNA to Evaluate Somatic Status), overcomes the cancer- and subclone-specific nature of these targeted approaches to provide a potential multi-cancer or clonal diagnostic to guide clinical decision making [ 37 ]. The application of existing technology to different cell types in liquid biopsies also has the potential to improve ctDNA biomarker performance in detecting disseminated cancer cells derived from heterogeneous tumors. For example, comparative deep sequencing of ctDNA and matched healthy hematopoietic cell DNA from patients with highly clonal lung tumors was more accurate in predicting patient prognosis compared to ctDNA analysis alone [ 38 ]. In addition, combining ctDNA biomarkers with existing imaging modalities, such as specialized positron emission tomography - computed tomography (PET–CT), can improve the sensitivity and specificity of micrometastasis detection [ 38 ], suggesting that a multifaceted approach may achieve clinical benefit in the near term.

While ctDNA analysis is a promising technology for indirectly detecting DTCs, it cannot indicate their discrete anatomical location, thereby limiting its application as a stand-alone diagnostic tool. Fragmentomics and epigenetic profiling of ctDNA are emerging fields of investigation that have the potential to overcome these limitations by enabling identification of the ctDNA organ of origin, and therefore the primary tumor location [ 39 , 40 ]. Fragmentomics analysis is founded on the principles that DNA fragmentation occurs in a tissue-specific manner due to the influence of nucleosomal organization, chromatin structure, gene expression, and nuclease content of the tissue of origin, resulting in characteristic organ-specific signatures of ctDNA fragment size, nucleotide motifs at the fragment ends, and the genomic locations of the fragmentation endpoints [ 40 ]. Similarly, the detection of aberrant epigenetic methylation patterns, which are more prevalent and penetrant than genetic mutations in ctDNA, provides a more sensitive detection of ctDNA than mutational analysis alone, and also indicates tissue of origin [ 39 ]. However, methylome analysis is not yet capable of indicating the location of metastatic sites. With over 20 currently active clinical trials evaluating ctDNA methylation in the diagnosis and monitoring of various cancers (as of April 2021), the development of these ctDNA detection approaches holds immense promise not only in monitoring metastatic dissemination but also in cancer diagnosis.

The monitoring of circulating protein markers and extracellular vesicles derived from cancer cells are also being developed as markers of tumor burden and as surrogates for metastatic disease in tumors that have been surgically resected, for example, CA19-9 in pancreatic cancer [ 41 ]. However, circulating levels of primary tumor markers alone are not always predictive of metastatic prognosis, such as biochemical recurrence in prostate cancer as indicated by PSA levels [ 42 ]. By specifically detecting secreted factors and extracellular vesicles derived from micrometastatic sites or those that play a critical role in priming distant pre-metastatic niches [ 20 , 22 , 24 , 43 – 45 ] it may be possible to monitor for metastatic propensity and likely secondary sites at earlier stages of recurence. For example, integrin signatures of tumor-derived exosomes orchestrate tumor cell organotropism [ 46 ] and, together with other exosomal protein and miRNA cargos, educate resident cells such as Kupffer cells, BMDCs, fibroblasts and endothelial cells to promote metastasis [ 19 , 22 , 44 – 46 ]. Importantly, high levels of exosomal proteins and miRNAs involved in pre-malignant niche establishment correlate with poor prognosis and higher risk of metastatic disease [ 19 , 22 , 44 – 46 ]. Therefore, the use of metastatis-specific protein- and RNA-based biomarkers may leverage existing diagnostic technology to enable monitoring of metastatic burden throughout treatment.

Translating disseminated tumor cell burden into clinical risk measures

While the DTC burden reflects the potential for metastatic disease to develop, the establishment of overt metastasis from CTCs and micrometastases is a highly inefficient process [ 47 ]. For example, in breast cancer, less than half of the patients with detectable micrometastases in the bone marrow develop distant recurrence within 10 years [ 48 ]. Therefore, the volume of disseminated disease when present as small cell clusters or single cells does not always directly correlate with the incidence of overt metastasis. Seminal studies have begun to dissect the key intrinsic tumor cell features that confer the capacity to form overt metastases, and have shown that these features are present in a specific subset of tumor cells [ 49 ]. This highlights a need to understand the cell intrinsic and extrinsic factors that act in concert with the disseminated disease burden to define a patient’s metastatic propensity.

Different secondary sites have different propensities for the development of overt recurrence [ 50 ]. For example, lymph nodes, liver, lung, and bone are common metastatic sites across a multitude of primary cancer types, yet overt metastases in skeletal muscle are relatively rare [ 51 ]. While the mechanisms underlying these patterns are not yet well defined, it is known that the site at which metastasis develops can impact survival outcomes; therefore, the discovery of biomarkers indicative of the secondary seeding site(s) will be critical to evaluate the risk of site-specific recurrence [ 52 – 54 ]. Information from rapid autopsies will be fundamental to our understanding of these processes and in identifying site-specific biomarkers. Furthermore, the role of broader host and environmental factors in promoting metastasis, such as surgical removal of the primary tumor, age- and biomechanics-induced bone remodeling, as well as systemic stress hormones, are still emerging [ 55 – 60 ]. To robustly capture the long-term metastatic risk on this complex background, clinical studies will need to follow large cohorts over a sufficiently long period of time. This long-term data can then be used to understand the effects of these myriad factors on metastatic risk and will underpin the implementation of biomarkers in future precision medicine approaches.

Understanding and modelling the dynamics of metastatic dissemination

Research autopsies: an abundant resource to study human metastasis.

Successfully dissecting and targeting the mechanisms that drive metastasis will depend on (1) a foundational understanding of metastasis mechanisms in patients, as well as (2) our ability to model metastasis in the laboratory. DTCs are difficult to detect, and secondary tumors at distant sites are often not surgically resected. Therefore, viable human tissue for researching metastasis mechanisms is scarce. Furthermore, as described above, assessing DTC/micrometastatic burden in patients and identifying features distinguishing indolent from aggressive DTCs has remained challenging. Research autopsies, also termed ‘warm’ or ‘rapid’ autopsies, of deceased cancer patients (1–6 h post-mortem) reveal the burden of disseminated disease at the end stages of disease and represent a valuable source of viable metastatic tissue [ 61 ]. The high integrity of tissues derived from research autopsies enables broad multi-omics analysis at the bulk and single cell resolutions to study cancer cells within the metastatic microenvironment. Importantly, research autopsies enable the establishment of patient-derived xenografts, cell lines and organoids for mechanistic studies [ 61 ]. Increased establishment of research autopsy protocols will require the multidisciplinary involvement of clinicians and researchers, together with the generosity of cancer patients and their families, in an effort that will continue to provide invaluable insight into metastatic burden and its drivers.

Technological advances revealing tumor heterogeneity and spatial compartmentalization of the metastatic microenvironment

Emerging advances point to cellular heterogeneity and the microenvironment of primary tumors, pre-metastatic niches and metastatic sites as having a profound influence on the propensity and dynamics of metastatic dissemination. Interactions between cancer, stromal and immune cells as well as with the extracellular matrix spatiotemporally regulate metastasis [ 62 , 63 ]. In this regard, the advent of single cell genomics and spatial profiling technologies are revolutionizing our understanding of cellular heterogeneity, cellular interactions and microenvironmental characteristics that support and promote metastasis.

Tumor heterogeneity and the evolution of highly metastatic subclones during the progression of heterogeneous tumors is thought to significantly contribute to metastatic propensity. Bulk analysis approaches have revealed specific mutational profiles and cellular states associated with polyclonal and monoclonal metastasis mechanisms in multiple cancer types [ 64 – 67 ]. More recently, single cell genomics approaches have been revolutionary in further revealing cellular subtypes within the broader heterogeneous tumor community that drive metastatic dissemination. For example, single cell RNA sequencing (scRNA-seq) of primary and metastatic patient-derived xenografts (PDXs) of mammary and lung tumors revealed an enrichment of stem-like/progenitor cell states in cancer cells within metastases as compared to primary tumors [ 68 , 69 ]. Due to its single-cell resolution, single cell genomics will be particularly relevant in identifying mutationally- and transcriptionally-driven mechanisms of therapy resistance operating in subclonal cells that then outgrow treatment-sensitive subclones to drive continued tumor progression. For instance, single cell genomics was applied to chemo-refractory triple negative breast tumors, which revealed that resistant genotypes exist prior to neoadjuvant chemotherapy, and transcriptional programs that emerge in resistant cancer cell populations are induced by the treatment [ 70 ]. Using single-cell genomics in therapy-naïve primary lesions and paired, pan-resistant, anachronous secondary tumors in patient samples seems a challenging endeavor, but will significantly expand our understanding on therapy evasion mechanisms in metastasis.

Insights derived from early laser capture microdissection profiling of the tumor microenvironment have been accelerated by the application of multiplexed imaging (e.g. CODEX [ 71 ]), spatial transcriptomics (including the commercially available 10x Genomics Visium platform and emerging technologies slide-SEQ, non-destructive FISSEQ) and spatial proteomics analysis (e.g. imaging mass spectrometry) [ 72 ], together with the layering of these technologies on the more mature bulk and single cell genomics approaches. For example, multiplex imaging coupled with next generation sequencing has revealed that the close proximity of highly proliferative cancer cells with specific lymphocyte subtypes regulate immunological surveillance as metastases develop [ 73 ]. More detailed spatial characterization is now afforded by multiplexed ion beam imaging (MIBI)[ 74 , 75 ], which harbors greater spectral depth than traditional fluorescence-based multispectral imaging, to enable the spatial identification of approximately 40 proteins within the microenvironment. This targeted technology has been integrated with spatial transcriptomics and single cell RNAseq in primary cutaneous squamous carcinoma to reveal the importance of spatially regulated cellular crosstalk nodes in tumorigenesis [ 76 ], demonstrating the potential of this approach in revealing key spatial relationships within tumors that could provide invaluable insight when specifically applied to metastatic disease.

Mass spectrometry imaging further extends the capacity of MIBI by mapping hundreds to thousands of metabolomic and proteomic analytes across tissue sections. Importantly, this technology identifies metabolic and proteomic features that cannot be obtained using the nucleotide-based spatial mapping technologies described above [ 77 ]. While metabolic and proteomic mass spectrometry imaging detection has been established for some time, recent improvements in sample preparation methods that more effectively preserve native tissue structure are unlocking the immense potential of this technology to reveal novel functional nodes of cell-cell and cell-matrix interactions governing metastatic processes [ 78 ]. This approach is particularly powerful in the burgeoning era of immunotherapy, where the interaction of cancer and immune cells is increasingly recognized to regulate metastasis. Recently, focused approaches have revealed a role for myeloid cells in activating dormant DTC proliferation through spatially compartmentalized laminin proteolysis [ 57 , 58 ] and lipid metabolism [ 56 ]. Further spatial profiling of these environments using the wide lens conferred by mass spectrometry imaging may identify additional local nodes of cell-cell interactions that together regulate anti-tumor surveillance in a nuanced, microenvironment-specific manner. These advances in spatial technologies will be critical to provide fundamental answers to (1) how the immune milieu influences metastatic burden and (2) how these processes can be harnessed to control metastasis using existing and novel immunotherapy approaches. Insights into both metabolic and ECM remodeling within and surrounding tumor cells gained from mass spectrometry imaging also have the potential to reveal actionable stromal co-targeting approaches to improve treatment sensitivity [ 7 , 79 ]. Overall, orthogonal spatial technologies have great potential to reveal novel mechanisms driving metastatic dissemination, which will underpin patient risk predictions and the development of metastasis-specific therapies.

Modelling metastasis to predict risk

The identification of tumor features that support metastasis and predict metastatic risk in patients will facilitate improvements in vitro [ 80 , 81 ] and in vivo models [ 82 , 83 ] that recapitulate the dynamics of metastatic dissemination, colonization and outgrowth. Patient-derived xenografts and three-dimensional organoid cultures derived during treatment and from research autopsies more accurately reflect clinical treatment responses, and are currently being implemented as patient avatars in precision medicine programs to identify the most effective treatment for individual patients [ 84 , 85 ]. As patient avatars, these models can be subjected to extensive drug screening in the laboratory to identify the most effective anti-tumor therapies that are likely to achieve a complete clinical response, thereby informing clinical practice to accelerate treatment. Improvements in animal models, including transplantable syngeneic mouse and human cancer lines, mouse xenografts, and genetically engineered- and humanized- mouse models are also being developed to mimic the behavior of human metastatic disease [ 86 , 87 ]. While models of primary tumor behavior have received considerable attention and have significantly contributed to developments in cancer treatment, investment in developing metastasis-specific preclinical models should be prioritized for their capacity to reveal metastatic mechanisms that can be readily exploited therapeutically to improve patient survival. These technological developments are anticipated to most profoundly impact poor prognosis cancers and disadvantaged populations where stage IV diagnoses are more prevalent.

Data gathered from preclinical and clinical studies of metastasis dynamics are underpinning the implementation of mathematical modelling and artificial intelligence to build computational predictors of metastatic burden and therapy response [ 88 ]. These mathematical models also confer the opportunity to infer the actual stage of progression for a patient’s tumor at diagnosis, to predict their likely burden of disseminated disease and to assess their risk of developing overt metastases [ 89 ]. Importantly, mathematical models have validated the non-linear relationship between primary tumor size and survival, indicating that metastatic propensity is not simply a function of tumor size but that tumor intrinsic, extrinsic and host factors all contribute to metastatic progression [ 90 ]. Furthermore, clinically-informed mathematical models can define when metastases develop to enable earlier metastasis detection. For example, models of brain metastases from primary lung tumors have identified that DTCs in the brain remain dormant for approximately 5 months before their outgrowth, and that a further 12-19 months of secondary tumor growth occurs before metastasis is clinically diagnosed [ 91 ], thereby indicating that there is a significant window of opportunity to inhibit the outgrowth of disseminated cancer cells to the brain as well as improve the detection of early brain metastases. This temporal understanding, coupled with the predictive power of these models [ 89 ], provides the foundation to improve protocols for the early detection of metastatic disease and reveals opportunities to treat these patients earlier than current protocols allow. Mathematical models that are able to integrate the myriad host-, tissue- and niche-specific factors in metastatic dissemination and outgrowth will be key to understanding, as well as predicting, how these microenvironmental factors interact with intrinsic features of a patient’s primary tumor to drive the organotypic nature of metastasis [ 92 ]. Fueled by increased clinical data collection, these modelling approaches represent a step towards the clinical implementation of mathematical modelling as a predictive tool in precision oncology.

Improving the treatment of metastatic disease

There are fundamental challenges in treating metastatic disease once it has been diagnosed. Tumor heterogeneity enables the persistence and expansion of treatment -refractory subclones at not only primary but also secondary sites. In addition, most current treatments are targeted to proliferative cell states, and therefore are less effective against quiescent metastatic disease prior to outgrowth. Disseminated disease, particularly when dormant, is commonly resistant to current standard-of-care therapies that target the primary tumor [ 93 ]. This enables residual disease to persist and re-emerge even after successful treatment of the primary tumor. Therefore, overcoming therapy resistance is paramount to prolonging the survival of metastatic patients.

Therapies that specifically target metastatic disease can be distinguished into two main categories: (1) treatments aimed at eradicating metastatic disease [ 29 ] and (2) treatments aimed at maintaining metastatic disease in a chronically dormant state [ 94 ].

Treatments aimed at eradicating metastatic disease

Metastatic tumors have higher levels of resistance to systemic conventional chemotherapies compared with primary tumors and this presents a major hurdle to eradicating metastatic disease [ 95 ]. Resistance mechanisms to conventional chemotherapies can be due to chemotherapy-induced acquisition of de novo genomic alterations [ 96 ], phenotypic adaptation to cytotoxic stress [ 97 ] or result from the expansion of pre-existing clones [ 98 ]. These resistance traits can arise during both the latent and overt stages of metastases [ 93 ].

Given that conventional chemotherapies indiscriminately target rapidly dividing cells, it was assumed that DTCs in a quiescent or dormant state would be relatively insensitive to cytotoxic therapies. Therefore, one approach to sensitizing dormant cells to conventional chemotherapies is to drive them into a highly proliferative state. Approaches to stimulate the awakening of dormant cells, including G-CSF and acute IFN-alpha treatments [ 99 , 100 ] or by driving epigenetic remodeling to transient drug-sensitive states (e.g. HDAC inhibition) [ 101 ], have improved the efficacy of cell cycle- and DNA damage response-dependent chemotherapeutic agents. However, these approaches carry a substantial risk of driving indiscriminate and uncontrollable metastatic outgrowth.

Recent data indicate that dormant cells can be targeted without the need to awaken them, thereby mitigating the significant risks associated with inducing them into a proliferative state. Rather than the quiescent state of dormant tumor cells giving rise to chemoresistance, these recent studies have identified cell-cell and cell-matrix interactions within the dormancy niche that protect DTCs from cytotoxic chemotherapies, independently of their proliferative state [ 9 , 102 ]. Such studies are beginning to reveal potential strategies for targeting these interactions to re-sensitize metastatic tumors to current standard-of-care agents without inducing uncontrolled metastatic outgrowth. Some of these approaches have the potential for near-immediate translation into clinical protocols. For example, additional rounds of docetaxel chemotherapy following standard-of-care fluorouracil, epirubicin, and cyclophosphamide (FEC) treatment eliminated dormant tumor cells in the bone marrow of some breast cancer patients [ 103 ], highlighting how additional rounds of currently available chemotherapies may be used to effectively prevent metastasis. Conversely, emerging evidence points to the ability of standard-of-care chemotherapy to potentiate metastatic dissemination and drive the awakening of dormant DTCs in specific in vivo models [ 8 ]. This contrasts with evidence that neoadjuvant chemotherapy has been shown to be as efficacious as adjuvant chemotherapy in terms of relapse-free survival in some cancers, and therefore a more thorough understanding of the effects of therapy on metastatic dynamics in patients should inform treatment strategies in the future. Finally, identification of survival mechanisms exercised by DTCs has revealed potential therapeutic targets including autophagy [ 104 ], Srk and Mek1/2 in combination [ 105 ], and integrin-signaling [ 62 , 102 ]. Overall, a more comprehensive understanding of these mechanisms is likely to reveal novel, specific targets of metastatic disease for further clinical development and provides hope that dormant DTCs can be eradicated without risking their uncontrolled proliferation.

Novel therapeutic strategies targeting metastasis are also emerging as our understanding of cancer cell-niche interactions develops. In bone metastases, identification of Jagged1 as a mediator of crosstalk between cancer cells and the bone microenvironment has led to the development of a new humanized anti-Jagged1 antibody that sensitizes bone metastases to chemotherapy [ 106 ]. Similarly, targeting integrin-mediated interactions in the perivascular niche of the bone microenvironment also prevents metastatic outgrowth in preclinical models [ 102 ]. Significant improvements in targeting metastatic disease will also rely on further development of nanoparticles and other chemotherapy carriers that can be targeted directly to specific secondary sites and pre-metastatic niches [ 17 ], thereby enabling combination therapies to simultaneously target multiple metastases. Defining how these niche-targeted treatments operate at different secondary sites and interact with each other will be critical in defining effective precision therapies.

Treatments enforcing dormancy

Given the challenges in eliminating dormant DTCs, and the low penetrance by which dormant DTCs manifest as overt metastases, developing therapies that maintain DTCs in a dormant state is regarded as a promising therapeutic approach. Estrogen receptor (ER) antagonists such as tamoxifen, commonly used to treat ER+ breast cancer, are an example of anti-metastatic therapies administered in an adjuvant setting, although it remains unclear whether this treatment maintains dormancy or enables the elimination of dormant cells. Studies of tamoxifen treatment for 10 years found an additional reduction in metastatic recurrence rates when compared to the standard-of-care 5-year treatment regimen [ 107 ], highlighting the potential for this approach to achieve long term remission. Similarly, RANKL inhibitors, such as denosumab, have demonstrated utility in reducing bone resorption-driven activation of dormant DTCs in bone metastases of prostate cancer [ 108 ].

More recent proposed approaches to enforce metastatic dormancy include small molecules and monoclonal antibody therapies that drive DTCs into a dormant state. Induction of DTC dormancy has been achieved through CDK4/6 inhibition (e.g. Palbociclib) [ 109 ] or by inhibiting outside-in pro-proliferative signaling [ 95 , 110 ]. Immunotherapy that harnesses immunological surveillance to control DTCs also has great potential to both eradicate and control metastatic disease since neutrophils and myeloid subtypes regulate microenvironmental cues that control dormancy [ 55 – 57 ]. For these reasons, immunotherapy is likely to become an essential component of metastasis management. Gaining a better understanding of the relationship between tissue-specific immune populations and DTCs, and how these interactions govern dormancy and outgrowth, will be essential to developing effective immunotherapies that control metastatic burden.

While treatments that eradicate or maintain cancer cell dormancy promise a future where metastatic latency can be effectively treated, therapies specifically targeting dormant metastatic disease are not yet clinically available. Fortunately, several clinical trials are ongoing with the explicit purpose of targeting dormancy and/or using DTCs or micrometastatic burden (for example, via detection of DTCs in bone marrow aspirates) as a readout of efficacy (Table  2 ). Nevertheless, substantial challenges remain in designing and completing clinical trials for metastasis-specific therapies. Regulatory frameworks around the world currently limit the feasibility of clinical trials with metastatic relapse at endpoints because the long time period required of such studies often exceeds that of intellectual property protection that underpins the financial support of the trial. Embarking on such a large and long trial is considered feasible when supported by substantial efficacy in the acute setting, and this hinders the development of cytostatic metastatic therapies that may not have substantial short term effects [ 97 ]. Furthermore, there must be a willingness from regulatory bodies to accept ctDNA and other biomarkers as clinical trial endpoints of metastasis, rather than the traditional RECIST-based progression-free survival readouts that encompass only overt metastases. The growing inclusion of disseminated disease burden as secondary endpoints in clinical trials will serve to (1) identify potential therapies for targeting dormancy after initial standard-of-care therapy has been completed and, (2) introduce the use of DTCs as a readout for therapeutic efficacy. Taken together, including disseminated disease burden in clinical trials is fundamental to developing more effective treatments against metastatic disease.

Interventional clinical trials targeting metastatic disease

Concluding remarks

Metastatic disease remains the major cause of cancer death, yet in most cancer types we are only beginning to understand the processes that govern the dissemination of cancer cells from the primary tumor, their seeding to distant sites and their eventual outgrowth into overt metastases. It is a significant challenge to dissect the numerous host, environmental and microenvironmental factors that intersect with intrinsic features of cancer cells to spatiotemporally regulate metastatic progression. However, our ability to accurately detect DTCs and garner an accurate measure of metastatic burden in patients throughout treatment will underpin efforts to treat metastatic disease more effectively (Challenge 1). On this front, substantial strides have been made in improving the sensitivity of metastatic detection through machine-learning fueled pathological assessment and the use of liquid biopsy biomarkers to collectively detect CTCs in patients. Standardization of these approaches, together with increased access to research autopsies, will illuminate a hitherto opaque understanding of metastatic dynamics and will predict which patients are likely to develop metastatic recurrence (Challenge 2). This clinical data will continue to inform accurate in vitro and in vivo modelling of metastasis, to dissect the complex spatiotemporal interplay of cell intrinsic, microenvironmental and host factors (Challenge 3). Patient avatars developed from these models most accurately represent the patient’s treatment response and could become central to precision medicine frameworks that identify the most effective treatment for each individual. With further standardization, these tools may also prove fundamental to drug development pipelines for metastasis-targeted therapies. Dose-intensity modulation of existing therapies or novel therapies that eradicate or suppress metastases are being developed as biological mechanisms governing these processes are revealed (Challenge 4). Ultimately, translating these treatments to the clinic will require large, long-term clinical trials capable of supporting the complexity of individualized precision medicine protocols and with disseminated tumor burden, at both the micro- and macro-metastatic scales, as primary endpoints. Continued progress in overcoming these major challenges will require the collective interdisciplinary effort of researchers, clinicians, patients and funding agencies to transform metastatic cancer into a highly manageable and ultimately curable disease in all patients across all cancer types.

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Amelia L. Parker and Early Career Leadership Council of the Metastasis Research Society have contributed eqully to this study.

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Metastasis Research Network (MetNet) 

Understanding the spectrum of complex metastatic processes is important to the development of a comprehensive and cohesive understanding of cancer metastasis. The Metastasis Research Network (MetNet) supports several U54 Specialized Centers ( RFA-CA-20-029 ). These collaborative, multidisciplinary projects focus on several themes of the metastatic process and utilize integrative systems-level approaches.

The MetNet will advance the understanding of metastasis as a non-linear, dynamic, and emergent process and promote advances in mechanistic understanding of early dissemination, cellular and physical microenvironment crosstalk, dormancy, and mechanisms of responses by metastatic cells to therapies. The network integrates multiple perspectives and expertise to advance metastasis research, including scientific experts in different fields, physicians, and research advocates.

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The advocates have three primary roles: 

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• Mentor researchers to broaden their understanding of the disease, help them communicate their work in a way that is accessible for those outside the scientific community, and gain perspective on the impact they have on patients’ lives. 
• Serve as a liaison to their communities by translating the progress of scientific research from MetNet for a general audience.

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• Andrey Rubanov (NYU Langone Health):  Chromatin remodeling by CHD7 regulates melanoma metastasis and anti-tumor immunity 

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Promising New Treatment for Patients with HR+ HER-2 Negative Metastatic Breast Cancer

Metastatic breast cancer image.

Breast cancer that has spread to other parts of the body ( metastatic ) is particularly hard to treat. New research from Yale Cancer Center reveals first-of-its-kind data from a phase I study in patients with hormone receptor positive HER2-negative metastatic breast cancer. The results, which assess the safety and efficacy of a treatment known as PF-07248144, offer new hope for treating this aggressive type of breast cancer.

Yale researchers found that PF-07248144, both as a standalone therapy and in combination with the hormone therapyfulvestrant (an estrogen receptor antagonist agent), was well-tolerated and effective at treating patients with hormone receptor-positive, HER2-negative metastatic breast cancer. PF-07248144 targets and blocks the proteins KAT6A and KAT6B, which can help cancer grow and spread when they are not working properly, or are dysregulated.

Senior author of the study, Patricia LoRusso, DO , Associate Director for Experimental Therapeutics at Yale Cancer Center, will present the findings at the American Society of Clinical Oncology (ASCO) Annual Meeting on June 1.

“We're now realizing how important epigenetics (field of study focused on modification of gene expression rather than the alteration of the underlying DNA) is in terms of understanding the biology of cancer and targeting the disease for treatment interventions,” said LoRusso.

For nearly three years, 107 patients were enrolled in the phase I trial and received at least one dose of PF-07248144. 29 patients received PF-07248144 at 5 dose levels, 35 patients received PF-07248144 at 5 mg daily, and 43 patients received PF-07248144 at 5 mg daily in combination with 500 mg fulvestrant. According to LoRusso, “the goal of the study was to overcome the patient’s ESR1 mutation and enhance, or resume response in combination with hormonal therapy (fulvestrant).”

In a review of the data, the combination of PF-07248144 with fulvestrant showed an objective response rate (ORR) of 30.2% and a median duration of response (DOR) of nine months. For patients who were treated with only PF-07248144, the ORR was lower at 11%, however the median DOR was slightly better at 12 months. Most side effects related to the treatment were manageable. The most common were taste alteration, a decrease in white blood cell count, and anemia.

The phase I trial is still ongoing, however the preliminary findings are encouraging and support further research of PF-07248144 in larger trials.

“Although this was not a randomized trial, the degree and duration of response of the combination of PF-07248144 with fulvestrant appear at least preliminarily in this trial to be better than historical data with fulvestrant alone,” said LoRusso.

Toru Mokuhara from National Cancer Hospital East in Kashiwa, Japan, was the study’s first author. Other authors include Yeon Hee Park, David Sommerhalder, Kan Yonemori, Erika Hamilton, Sung-Bae Kim, Jee Hyun Kim, Hiroji Iwata, Toshinari Yamashita, Rachel M. Layman, Timothy Clay, Yee Soo Chae, Catherine Oakman, Fengting Yan,Gun Min Kim,Seock-Ah Im, Geoffrey J. Lindeman, Hope S. Rugo, Marlon Liyanage, Michelle Saul, Christophe Le Corre, Athanasia Skoura, Li Liu, and Meng Li.

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Stopping the spread: A revolution in how we think about metastasis

18 October 2022

When a cancer spreads from a primary tumour, the place where it first started to grow, to another area of the body, this is referred to as metastasis .  

To spread, some cells from a primary tumour need to break away and travel to another place in the body via the bloodstream. These cells then form another tumour, called a secondary tumour, in another organ.   

For example, breast cancer cells may travel to the lungs and form a secondary tumour there.   

Metastasis is associated with very poor prognosis, and despite being the main cause of death in people with cancer, it has remained incredibly difficult to prevent and treat. This is largely because we haven’t been able to identify key drivers of this process that could act as therapeutic targets. Until now.  

Ground-breaking research from scientists at our Cambridge Institute, recently published in Nature Genetics , has identified a protein in our cells, called NALCN, as a key regulator of metastasis.  

What’s more, their findings show us that metastasis isn’t a process unique to cancer cells. Instead, cancer cells exploit a process that healthy tissues use to shed cells and move around the body, revolutionising the way we think about metastasis.  

These findings are among the most important to have come out of my lab for three decades. Not only have we identified one of the elusive drivers of metastasis, but we have also turned a commonly held understanding of this on its head, showing how cancer hijacks this process in healthy cells for its own gains.   Professor Richard Gilbertson  

Finding the right channel  

In their previous research, the team had identified a gene that was ‘turned off’ when a normal stem cell became a malignant stem cell in stomach cancers.   

That gene makes the protein NALCN, which is a channel in the membrane of our cells that lets tiny molecules of salt pass in and out of them. The mutations caused the channel to be blocked off so it can’t perform its usual function.  

This was unexpected, as the normal function of NALCN seemed to have no bearing otherwise on cancer development or progression.   

So, in their most recent study they tested the effect of switching off this gene in mice with gastrointestinal cancers.  

What they found was that losing the function of this gene had no effect on the primary tumour, but it caused the cancer to become extremely metastatic.   

To investigate this phenomenon further, they switched the gene off in mice without cancer. And that’s where things got more interesting.   

In these mice that had no NALCN, they found that healthy cells were metastasising around the body at a level similar to that of tumour cells in the mice with cancer.   

Crucially, when these circulating cells reached another organ, they formed normal tissue in that organ. For example, if cells that had shed from the stomach had moved to the kidney, they turned into normal kidney cells.   

“Traditionally, we think about our organs a bit like houses in a street, and those houses never share bricks with each other throughout life,” says Professor Richard Gilbertson, senior group leader at our Cambridge Institute.   

“What this opens the possibility for is that organs can actually share their cells with each other.   

“In fact, we see this at low rates going on all the time, even when we don’t delete this channel, suggesting that organs actually are much more fluid than we used to think.”  

It may be that the body is therefore using this process as a repair mechanism. If some of the cells in one organ are damaged, cells from other organs can be mobilised to replace them.  

This is the first time it’s been shown that metastasis is in fact a normal process, and it’s not only cancer cells that can spread around the body, a belief that’s been held for decades.  

Solving the mysteries  

In addition to elucidating the mechanism of metastasis, these findings might help to explain other current mysteries surrounding metastasis. For example, secondary tumours can appear in a person that had their primary tumour removed many years earlier or, in very rare cases, never had a primary tumour.  

In these cases, it may be that healthy cells acquired some cancer-causing mutations but did not develop into cancer at their primary location. These ‘normal’ cells then shed from their original site, and move to other organs, where they formed normal tissue.   

These cells then go on to become cancerous in the future after accumulating more mutations, creating metastases even though a primary tumour has been removed, or never formed in the tissue they originally came from.   

And on the flipside, it provides an explanation as to why, for many years, dormant circulating tumour cells (CTCs) have been observed in people with cancer that have not gone on to form secondary tumours, which raised the question of why some CTCs form tumours and others don’t.  

It’s because these circulating cells aren’t actually tumour cells, they’re cells from healthy tissues, we just didn’t know they could circulate before now.   

“We’ve been tied to the concept that this has to be abnormal, therefore, they have to be cancer cells,” says Gilbertson. “But now we know that isn’t the case. They’re not tumour cells, they’re actually part of this normal process.”  

Opening the possibilities  

Having identified the driver of metastasis, we now have a potential therapeutic target for preventing it, which has huge implications for cancer survival.  

The team are therefore looking into ways to restore the function of NALCN in cancer cells to prevent metastasis from occurring.   

This might be tricky, as drugs that target this type of channel usually aim to block them, rather than hold them open. However, it has been achieved before in drugs used to treat other conditions like cystic fibrosis, and the team are investigating whether there are existing drugs that could be repurposed to prevent metastasis.  

But that isn’t the only implication of this research.  

“We’ve got lots of different avenues to explore,” says Dr Eric Rahrmann, lead researcher on the study and senior research associate at our Cambridge Institute.  

“Can we use the mutations in this gene as a diagnostic marker? Like an early detection approach. Can we make predictions on whether people will have metastatic disease?  

“We’re also looking at regenerative therapy medicines. If we enhance dissemination of cells from one organ to go into another organ to repair it, can we use this more as a truly reparative mechanism?”  

This discovery has the potential to truly change the research landscape, both in the field of cancer research and beyond.  

“If you could stop metastasis,” Gilbertson concludes. “Or significantly suppress it, you’re getting towards managing cancer for the long term, and that’s the Holy Grail.”  

This is such an amazing discovery and really great news. I do so enjoy reading about the fantasic work being done by CRUK and associated research groups.

I have been reading your observations which clearly show great strides in your work which show great advancement in your research.

Keep up the good work so eventually you will develop enough experience gained from trials with mice to start trials in humans .

I am thrilled beyond words with this progress albeit nearly 8 years too late for my beloved husband

I hope and pray that this study can be fast tracked. If meds for Covid came so fast I truly hope this can too. Think of the lives that could be saved. As I’m living with MBC and also living with HOPE.

They need to realize time is critical. My young daughter has mtnbc and will likely never make it as “oversight” agencies spend years and years dragging things out. They will never convince me this is necessary for something absolutely lethal…

As someone living with MBC I am hopeful and thankful to all who are working to eradicate this horrible disease. A lot of these discoveries may not come to fruition in time for me with human trials but I am thankful that they may save so many lives.

Excellent news and as a stage IV breast cancer patient some inspirational news. Let’s have the drug available sooner than later please.

Amazing news about metastatic cancer Hopefully one day it can be treated and controlled, if not cured

An extremely exciting decision development!

This is fantastic research, congratulations to the team. Any chance we can get it fast tracked so that we are not waiting at least 10 years before it can save lives, either through repurposed drugs or novel drugs. We need urgent action now to save life and end the terrible suffering currently taking place with this disease.

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Gene variants foretell the biology of future breast cancers in Stanford Medicine study

In a finding that vastly expands the understanding of tumor evolution, researchers discover genetic biomarkers that can predict the breast cancer subtype a patient is likely to develop.

May 30, 2024 - By Krista Conger

Stanford Medicine researchers found that inherited gene sequences can predict what type of breast cancer a patient is likely to develop, along with how aggressive that cancer may be.   Emily Moskal

A Stanford Medicine study of thousands of breast cancers has found that the gene sequences we inherit at conception are powerful predictors of the breast cancer type we might develop decades later and how deadly it might be.

The study challenges the dogma that most cancers arise as the result of random mutations that accumulate during our lifetimes. Instead, it points to the active involvement of gene sequences we inherit from our parents — what’s known as your germline genome — in determining whether cells bearing potential cancer-causing mutations are recognized and eliminated by the immune system or skitter under the radar to become nascent cancers. 

“Apart from a few highly penetrant genes that confer significant cancer risk, the role of hereditary factors remains poorly understood, and most malignancies are assumed to result from random errors during cell division or bad luck,” said Christina Curtis , PhD, the RZ Cao Professor of Medicine and a professor of genetics and of biomedical data science. “This would imply that tumor initiation is random, but that is not what we observe. Rather, we find that the path to tumor development is constrained by hereditary factors and immunity. This new result unearths a new class of biomarkers to forecast tumor progression and an entirely new way of understanding breast cancer origins.”

Curtis is the senior author of the study, which will be published May 31 in Science . Postdoctoral scholar Kathleen Houlahan , PhD, is the lead author of the research.

“Back in 2015, we had posited that some tumors are ‘born to be bad’ — meaning that their malignant and even metastatic potential is determined early in the disease course,” Curtis said. “We and others have since corroborated this finding across multiple tumors, but these findings cast a whole new light on just how early this happens.”

A new take on cancer’s origin

The study, which gives a nuanced and powerful new understanding of the interplay between newly arisen cancer cells and the immune system, is likely to help researchers and clinicians better predict and combat breast tumors.

Currently, only a few high-profile cancer-associated mutations in genes are regularly used to predict cancers, but these account for a small minority of cases. Those include BRCA1 and BRCA2, which occur in about one of every 500 women and confer an increased risk of breast or ovarian cancer, and rarer mutations in a gene called TP53 that causes a disease called Li Fraumeni syndrome, which predisposes to childhood and adult-onset tumors.

Christina Curtis

The findings suggest there are tens or hundreds of additional gene variants — identifiable in healthy people — that through interactions with the immune system pull the strings that determine why some people remain cancer-free throughout their lives.

“Our findings not only explain which subtype of breast cancer an individual is likely to develop,” Houlahan said, “but they also hint at how aggressive and prone to metastasizing that subtype will be. Beyond that, we speculate that these inherited variants may influence a person’s risk of developing breast cancer. However, future studies will be needed to examine this.”  

The genes we inherit from our parents are known as our germline genome. They’re mirrors of our parents’ genetic makeup, and they can vary among people in small ways that give some of us blue eyes, brown hair or type O blood. Some inherited genes include mutations that confer increased cancer risk from the get-go, such as BRCA1, BRCA2 and TP53.

In contrast, most cancer-associated genes are part of what’s known as our somatic genome. As we live our lives, our cells divide and die in the tens of millions. Each time the DNA in a cell is copied, mistakes happen and mutations can accumulate. DNA in tumors is often compared with the germline genomes in blood or normal tissues in an individual to pinpoint which changes likely led to the cell’s cancerous transformation.

Classifying breast cancers

In 2012, Curtis began a deep dive — assisted by machine learning — into the types of somatic mutations that occur in thousands of breast cancers. She was eventually able to categorize the disease into 11 subtypes with varying prognoses and risk of recurrence, finding that four of the 11 groups were significantly more likely to recur even 10 or 20 years after diagnosis — critical information for clinicians making treatment decisions and discussing long-term prognoses with their patients.

Prior studies had shown that people with inherited BRCA1 mutations tend to develop a subtype of breast cancer known as triple negative breast cancer. This correlation implies some behind-the-scenes shenanigans by the germline genome that affects what subtype of breast cancer someone might develop.

“We wanted to understand how inherited DNA might sculpt how a tumor evolves,” Houlahan said. To do so, they took a close look at the immune system.

It’s a quirk of biology that even healthy cells routinely decorate their outer membranes with small chunks of the proteins they have bobbing in their cytoplasm — an outward display that reflects their inner style.

Kathleen Houlahan

The foundations for this display are what’s known as HLA proteins, and they are highly variable among individuals. Like fashion police, immune cells called T cells prowl the body looking for any suspicious or overly flashy bling (called epitopes) that might signal something is amiss inside the cell. A cell infected with a virus will display bits of viral proteins; a sick or cancerous cell will adorn itself with abnormal proteins. These faux pas trigger the T cells to destroy the offenders.

Houlahan and Curtis decided to focus on oncogenes, normal genes that, when mutated, can free a cell from regulatory pathways meant to keep it on the straight and narrow. Often, these mutations take the form of multiple copies of the normal gene, arranged nose to tail along the DNA — the result of a kind of genomic stutter called amplification. Amplifications in specific oncogenes drive different cancer pathways and were used to differentiate one breast cancer subtype from another in Curtis’ original studies.

The importance of bling

The researchers wondered whether highly recognizable epitopes would be more likely to attract T cells’ attention than other, more modest displays (think golf-ball-sized, dangly turquoise earrings versus a simple silver stud). If so, a cell that had inherited a flashy version of an oncogene might be less able to pull off its amplification without alerting the immune system than a cell with a more modest version of the same gene. (One pair of overly gaudy turquoise earrings can be excused; five pairs might cause a patrolling fashionista T cell to switch from tutting to terminating.)

The researchers studied nearly 6,000 breast tumors spanning various stages of disease to learn whether the subtype of each tumor correlated with the patients’ germline oncogene sequences. They found that people who had inherited an oncogene with a high germline epitope burden (read: lots of bling) — and an HLA type that can display that epitope prominently — were significantly less likely to develop breast cancer subtypes in which that oncogene is amplified.

There was a surprise, though. The researchers found that cancers with a large germline epitope burden that manage to escape the roving immune cells early in their development tended to be more aggressive and have a poorer prognosis than their more subdued peers.

“At the early, pre-invasive stage, a high germline epitope burden is protective against cancer,” Houlahan said. “But once it’s been forced to wrestle with the immune system and come up with mechanisms to overcome it, tumors with high germline epitope burden are more aggressive and prone to metastasis. The pattern flips during tumor progression.”

“Basically, there is a tug of war between tumor and immune cells,” Curtis said. “In the preinvasive setting, the nascent tumor may initially be more susceptible to immune surveillance and destruction. Indeed, many tumors are likely eliminated in this manner and go unnoticed. However, the immune system does not always win. Some tumor cells may not be eliminated and those that persist develop ways to evade immune recognition and destruction. Our findings shed light on this opaque process and may inform the optimal timing of therapeutic intervention, as well as how to make an immunologically cold tumor become hot, rendering it more sensitive to therapy.”

The researchers envision a future when the germline genome is used to further stratify the 11 breast cancer subtypes identified by Curtis to guide treatment decisions and improve prognoses and monitoring for recurrence. The study’s findings may also give additional clues in the hunt for personalized cancer immunotherapies and may enable clinicians to one day predict a healthy person’s risk of developing an invasive breast cancer from a simple blood sample.

“We started with a bold hypothesis,” Curtis said. “The field had not thought about tumor origins and evolution in this way. We’re examining other cancers through this new lens of hereditary and acquired factors and tumor-immune co-evolution.”

The study was funded by the National Institutes of Health (grants DP1-CA238296 and U54CA261719), the Canadian Institutes of Health Research and the Chan Zuckerberg Biohub.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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Keywords : Metastatic cascade, organ tropisms and colonization, primary tumor factors, extracellular vesicles, cancer cell dormancy, cancer treatment

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Scientists create tailored drug for aggressive breast cancer

Scientists have used breast cancer cells' weakness against themselves by linking a tumour-selective antibody with a cell-killing drug to destroy hard-to-treat tumours.

The research, published today in Clinical Cancer Research by a team from King's College London and funded by Breast Cancer Now, marks a new method in cancer treatment.

The discovery is particular to triple negative breast cancer, which makes up 15% of all diagnosed breast cancer. This type of breast cancer is typically aggressive, resistant to chemotherapy, has a lower survival rate and is more common in women under 40.

Usual treatment involves surgery, chemotherapy and radiotherapy, however this type of cancer can evade the drugs and return to spread again.

The scientists conducted data analysis using over 6000 breast cancer samples to investigate the properties of breast cancer cells that are associated with aggressive and chemotherapy-resistant cancers.

They studied the cancer's biology, what is expressed in the tumour and the cell surface, and the cell's insides to understand how the cancer cells escape from cancer drugs. They established the presence of the cancer cell surface marker EGFR along with oncogenic molecules cyclin-dependent kinases (CDK), which are responsible for cell division and proliferation.

They used this knowledge against the cancer cells to link cetuximab, a tumour-selective antibody that targets the EGFR protein expressed in this type of cancer, with a CDK-blocking drug to create a tailored drug for breast cancer. Because the antibody drug conjugate specifically targets the cancer cell, it may be possible to administer a lower inhibitor dose than usual which means it's less toxic for the patient.

Lead author Professor Sophia Karagiannis, from King's College London, said: "We were on the hunt for cancer's vulnerabilities and now we've found out how we can guide our therapies to one of these. We combined these two drugs to create a tailored antibody drug conjugate for patients with this aggressive cancer. The antibody guides the toxic drug directly to the cancer cell which offers the possibility for a lower dose and less adverse side effects to be experienced.

"More work needs to be done before this therapy can reach the clinic, but we expect that this can offer new treatment options for cancers with unfavourable prognosis. Beyond this antibody drug conjugate, we hope that our concept will lead the way for new antibody drug conjugates of this type to be tailored to patient groups likely to benefit."

Lead research scientist Dr Anthony Cheung from King's College London said: ''Triple negative breast cancer represents a molecularly and clinically diverse disease. By exploiting EGFR overexpression and dysregulated cell cycle molecules in selected patient groups, the antibody drug conjugate, but not the antibody alone, could stop the cancer cell from dividing and engender cytotoxic functions specifically against the cancer cells.''

Dr Simon Vincent, director of services, support and influencing at Breast Cancer Now, which funded this research, said: "Each year, around 8,000 women in the UK are diagnosed with triple negative breast cancer, which is typically more aggressive than other breast cancers and more likely to return or spread following treatment.

"This exciting research has not only improved our understanding of the properties of aggressive breast cancer cells that are resistant to chemotherapy but has also brought us closer to developing a targeted therapy that destroys these cancer cells while minimising side effects for patients.

"While further research is needed before this treatment can be used in people, this is an exciting step forward in developing targeted therapies for triple negative breast cancer, and we look forward to seeing how these findings could lead to new and effective ways of tackling this devastating disease."

• Breast Cancer
• Lung Cancer
• Colon Cancer
• Brain Tumor
• Ovarian Cancer
• Monoclonal antibody therapy
• Chemotherapy
• Mammography
• Breast cancer
• Esophageal cancer

Story Source:

Materials provided by King's College London . Note: Content may be edited for style and length.

Journal Reference :

• Anthony Cheung, Alicia M. Chenoweth, Annelie Johansson, Roman Laddach, Naomi Guppy, Jennifer Trendell, Benjamina Esapa, Antranik Mavousian, Blanca Navarro-Llinas, Syed Haider, Pablo Romero-Clavijo, Ricarda M. Hoffmann, Paolo Andriollo, Khondaker Miraz Rahman, Paul Jackson, Sophia Tsoka, Sheeba Irshad, Ioannis Roxanis, Anita Grigoriadis, David E. Thurston, Christopher J. Lord, Andrew N.J. Tutt, Sophia N. Karagiannis. Anti-EGFR antibody-drug conjugate carrying an inhibitor targeting CDK restricts triple-negative breast cancer growth . Clinical Cancer Research , 2024; DOI: 10.1158/1078-0432.CCR-23-3110

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Pfizer drug extends life for people with rare form of lung cancer

A Pfizer lung cancer drug has been shown to greatly reduce tumor progression and improve survival outcomes for people in the advanced stages of a rare form of the disease, according to trial results published Friday.

Lorlatinib, which is already approved and available under the brand name Lorbrena in the United States, was tested in a clinical trial of hundreds of people with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).

Roughly half received lorlatinib while the rest received crizotinib, an earlier generation drug.

After five years of follow-up, more than half of patients treated with lorlatinib did not see their cancer progress.

"We're talking about patients with advanced metastatic disease—so this is actually a truly unprecedented finding," Pfizer's thoracic oncology strategy lead Despina Thomaidou told AFP.

Sixty percent of patients receiving lorlatinib, an oral one a day tablet, were alive without disease progression after five years compared to 8 percent on crizotinib.

"There is an 81 percent reduction in the risk of progression or death," added Thomaidou.

Lung cancer is the leading cause of cancer deaths globally.

NSCLC accounts for more than 80 percent of lung cancers, with ALK-positive tumors responsible for roughly five percent of NSCLC cases, translating to around 72,000 new cases each year worldwide.

ALK-positive NSCLC mostly affects younger patients and is not strongly linked to smoking. It is also very aggressive—25-40 percent of people with ALK-positive NSCLC develop brain metastases within the first two years.

Lorlatinib penetrates the blood-brain barrier better than prior generation medicines, said Thomaidou, and works to inhibit tumor mutations that drive resistance.

Patients on the lorlatinib arm had a 94 percent risk reduction in the progression of brain metastases compared to crizotinib.

Side effects of lorlatinib included swellings, weight gain and mental health problems such as depression.

"The progression-free survival is outstanding—we have not seen anything close to this," said oncologist David Spigel of Sarah Cannon Research Institute in Nashville, who was not involved in the study.

One critique he had was that lorlatinib was compared to crizotinib, which was "an outstanding drug in its time," but has since fallen out of use in the United States.

The results were published at the annual meeting of the American Society of Clinical Oncology and in the Journal of Clinical Oncology .

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Harvard-led study IDs statin that may block pathway to some cancers

Cholesterol-lowering drug suppresses chronic inflammation that creates dangerous cascade

Tracy Hampton

MGH Communications

Statins, commonly used cholesterol-lowering drugs, may block a pathway that leads to the development of cancer from chronic inflammation, according to a new study led by investigators from Harvard-affiliated  Mass General Cancer Center .

The team’s experiments showed that environmental toxins, such as those caused by exposure to allergens and chemical irritants, create a cascade effect that stimulates inflammation in the skin and pancreas that, when chronic, can result in cancer. Their findings suggest that using statins to suppress this pathway may have a protective effect.

The findings are published in Nature Communications.

In mice, pitavastatin suppressed environmentally induced inflammation in the skin and the pancreas and prevented the development of inflammation-related pancreatic cancers. 

“Chronic inflammation is a major cause of cancer worldwide,” said senior author Shawn Demehri, a principal investigator at the Center for Cancer Immunology and Cutaneous Biology Research Center of Massachusetts General Hospital and an associate professor of dermatology at Harvard Medical School and the Bob and Rita Davis Family MGH Research Scholar 2023-2028 .

“We investigated the mechanism by which environmental toxins drive the initiation of cancer-prone chronic inflammation in the skin and pancreas. Furthermore, we examined safe and effective therapies to block this pathway in order to suppress chronic inflammation and its cancer aftermath,” Demehri said.

The study relied on cell lines, animal models, human tissue samples, and epidemiological data. The group’s cell-based experiments demonstrated that environmental toxins (such as exposure to allergens and chemical irritants) activate two connected signaling pathways called the TLR3/4 and TBK1-IRF3 pathways. This activation leads to the production of the interleukin-33 (IL-33) protein, which stimulates inflammation in the skin and pancreas that can contribute to the development of cancer.

When they screened a library of U.S. Food and Drug Administration-approved drugs, the researchers found that the statin pitavastatin effectively suppresses IL-33 expression by blocking the activation of the TBK1-IRF3 signaling pathway. In mice, pitavastatin suppressed environmentally induced inflammation in the skin and pancreas and prevented development of inflammation-related pancreatic cancers. 

In human pancreas tissue samples, IL-33 was overexpressed in samples from patients with chronic pancreatitis (inflammation) and pancreatic cancer compared with normal pancreatic tissue. Also, in analyses of electronic health records data on more than 200 million people across North America and Europe, use of pitavastatin was linked to a significantly reduced risk of chronic pancreatitis and pancreatic cancer.

The findings demonstrate that blocking IL-33 production with pitavastatin may be a safe and effective preventive strategy to suppress chronic inflammation and the subsequent development of certain cancers.

“Next, we aim to further examine the impact of statins in preventing cancer development in chronic inflammation in liver and gastrointestinal tract and to identify other novel, therapeutic approaches to suppress cancer-prone chronic inflammation” said Demehri.

Research support was provided by the Burroughs Wellcome Fund, the LEO Foundation, the Sidney Kimmel Foundation, and the National Institutes of Health.

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• Published: 28 May 2024

Mechanisms of metastatic colorectal cancer

• Adrià Cañellas-Socias   ORCID: orcid.org/0000-0002-8373-7803 1 , 2   nAff4 ,
• Elena Sancho 1 , 2 &
• Eduard Batlle   ORCID: orcid.org/0000-0003-2422-0326 1 , 2 , 3  

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Despite extensive research and improvements in understanding colorectal cancer (CRC), its metastatic form continues to pose a substantial challenge, primarily owing to limited therapeutic options and a poor prognosis. This Review addresses the emerging focus on metastatic CRC (mCRC), which has historically been under-studied compared with primary CRC despite its lethality. We delve into two crucial aspects: the molecular and cellular determinants facilitating CRC metastasis and the principles guiding the evolution of metastatic disease. Initially, we examine the genetic alterations integral to CRC metastasis, connecting them to clinically marked characteristics of advanced CRC. Subsequently, we scrutinize the role of cellular heterogeneity and plasticity in metastatic spread and therapy resistance. Finally, we explore how the tumour microenvironment influences metastatic disease, emphasizing the effect of stromal gene programmes and the immune context. The ongoing research in these fields holds immense importance, as its future implications are projected to revolutionize the treatment of patients with mCRC, hopefully offering a promising outlook for their survival.

Despite metastatic disease being the main cause of death in colorectal cancer (CRC), its molecular basis remains poorly characterized, which hinders the development of therapeutic strategies.

Data support the view that most driver events necessary for metastatic dissemination are acquired early during cancer evolution; however, mutations in oncogenes and tumour suppressor genes influence metastatic disease progression.

Tumour cell plasticity is pervasive and necessary for metastatic progression; tumour cells co-opt different cell states during metastatic dissemination, relapse, outgrowth and therapy resistance.

Metastases show either an immune-excluded or an immune-desert phenotype, implying a major role of the immune system in shaping metastatic CRC; different metastases from the same patient might exhibit distinct immune environments.

A holistic view of immune evasion mechanisms in metastases is lacking, and emerging evidence suggests that metastases of different organs co-opt distinct tumour microenvironments and respond differently to immune therapies.

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Genetic and microenvironmental intra-tumor heterogeneity impacts colorectal cancer evolution and metastatic development

Molecular characterization of colorectal cancer related peritoneal metastatic disease

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Acknowledgements

The authors acknowledge the support of all members of the Batlle Laboratory. E.B. receives support from ERC (ERC AdvG 884623), AGAUR-SGR1278, Spanish Ministry of Science PID2020-119917RB-I00, IMI-PERSIST-SEQ, and AECC (GEACC19006BAT).

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Adrià Cañellas-Socias

Present address: Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA

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Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

Adrià Cañellas-Socias, Elena Sancho & Eduard Batlle

Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain

Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

Eduard Batlle

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All authors researched data for the article. E.B. and A.C.-S. contributed substantially to conceptualization of the content. All authors wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Adrià Cañellas-Socias or Eduard Batlle .

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E.B. is author in a patent related to TGFβ inhibitors. E.B. is author in a patent describing bispecific antibodies to target cancer stem cells. The laboratory of E.B. has received research funding from MERUS and INCYTE. E.B. has received honoraria for consulting from Genentech. The remaining authors declare no competing interests.

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Cañellas-Socias, A., Sancho, E. & Batlle, E. Mechanisms of metastatic colorectal cancer. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-00934-z

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DOI : https://doi.org/10.1038/s41575-024-00934-z

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