Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of metastasis-initiating cells that results in tumor growth in distant organs, evasion of immune surveillance and co-option of metastatic microenvironments. Here we review recent progress that is enabling therapeutic advances in treating both micro- and macrometastases. Such insights were gained from cancer sequencing, mechanistic studies and clinical trials, including of immunotherapy. These studies reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes.
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Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).
Caswell-Jin, J. L. et al. Change in survival in metastatic breast cancer with treatment advances: meta-analysis and systematic review. JNCI Cancer Spectr. 2, pky062 (2018).
Howlader, N. et al. (eds.) in SEER Cancer Statistics Review, 1975–2016 1423–1437 (National Cancer Institute, 2019).
May, M. Twenty-five ways clinical trials have changed in the last 25 years. Nat. Med. 25, 2–5 (2019).
Hosseini, H. et al. Early dissemination seeds metastasis in breast cancer. Nature 540, 552–558 (2016).
Harper, K. L. et al. Mechanism of early dissemination and metastasis in Her2+ mammary cancer. Nature 540, 588–592 (2016).
Hu, Z. & Curtis, C. Looking backward in time to define the chronology of metastasis. Nat. Commun. 11, 3213 (2020).
Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2, 563–572 (2002).
Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).
Massagué, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).
Quintanal-Villalonga, A. et al. Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nat. Rev. Clin. Oncol. 17, 360–371 (2020).
Laughney, A. M. et al. Regenerative lineages and immune-mediated pruning in lung cancer metastasis. Nat. Med. 26, 259–269 (2020).
Fumagalli, A. O. et al. Plasticity of Lgr5-negative cancer cells drives metastasis in colorectal cancer. Cell Stem Cell 26, 569–578 (2020).
Biswas, D. et al. A clonal expression biomarker associates with lung cancer mortality. Nat. Med. 25, 1540–1548 (2019).
Obenauf, A. C. & Massagué, J. Surviving at a distance: organ-specific metastasis. Trends Cancer 1, 76–91 (2015).
Esposito, M., Guise, T. & Kang, Y. The biology of bone metastasis. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a031252 (2018).
Boire, A., Brastianos, P. K., Garzia, L. & Valiente, M. Brain metastasis. Nat. Rev. Cancer 20, 4–11 (2020).
Celià-Terrassa, T. & Kang, Y. Metastatic niche functions and therapeutic opportunities. Nat. Cell Biol. 20, 868–877 (2018).
Turajlic, S. & Swanton, C. Metastasis as an evolutionary process. Science 352, 169–175 (2016).
Reiter, J. G. et al. An analysis of genetic heterogeneity in untreated cancers. Nat. Rev. Cancer 19, 639–650 (2019).
Razavi, P. et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell 34, 427–438 (2018).
Reiter, J. G. et al. Minimal functional driver gene heterogeneity among untreated metastases. Science 361, 1033–1037 (2018).
Sanchez-Vega, F. et al. Oncogenic signaling pathways in The Cancer Genome Atlas. Cell 173, 321–337 (2018).
Hu, Z., Li, Z., Ma, Z. & Curtis, C. Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases. Nat. Genet. 52, 701–708 (2020).
Jacob, L. S. et al. Metastatic competence can emerge with selection of preexisting oncogenic alleles without a need of new mutations. Cancer Res. 75, 3713–3719 (2015).
Denny, S. K. et al. Nfib promotes metastasis through a widespread increase in chromatin accessibility. Cell 166, 328–342 (2016).
Roe, J. S. et al. Enhancer reprogramming promotes pancreatic cancer metastasis. Cell 170, 875–888 (2017).
Vanharanta, S. et al. Epigenetic expansion of VHL–HIF signal output drives multiorgan metastasis in renal cancer. Nat. Med. 19, 50–56 (2013).
Tavazoie, S. F. et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451, 147–152 (2008).
Gomes, A. P. et al. Dynamic incorporation of histone H3 variants into chromatin is essential for acquisition of aggressive traits and metastatic colonization. Cancer Cell 36, 402–417 (2019).
McDonald, O. G. et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat. Genet. 49, 367–376 (2017).
Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124–1134 (2017).
Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).
Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730–737 (1997).
Shimokawa, M. et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 545, 187–192 (2017).
Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).
Visvader, J. E. Cells of origin in cancer. Nature 469, 314–322 (2011).
Oskarsson, T., Batlle, E. & Massagué, J. Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14, 306–321 (2014).
Ganesh, K. et al. L1CAM defines the regenerative origin of metastasis-initiating cells in colorectal cancer. Nat. Cancer 1, 28–45 (2020).
Altevogt, P., Doberstein, K. & Fogel, M. L1CAM in human cancer. Int. J. Cancer 138, 1565–1576 (2016).
Er, E. E. et al. Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization. Nat. Cell Biol. 20, 966–978 (2018).
Valiente, M. et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016 (2014).
Nieto, M. A., Huang, R. Y., Jackson, R. A. & Thiery, J. P. Emt: 2016. Cell 166, 21–45 (2016).
Yang, J. et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 21, 341–352 (2020).
Pastushenko, I. et al. Identification of the tumour transition states occurring during EMT. Nature 556, 463–468 (2018).
Shibue, T. & Weinberg, R. A. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 14, 611–629 (2017).
Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725–736 (2012).
Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial–mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724 (2012).
Su, J. et al. TGF-β orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1. Nature 577, 566–571 (2020).
Rickman, D. S., Beltran, H., Demichelis, F. & Rubin, M. A. Biology and evolution of poorly differentiated neuroendocrine tumors. Nat. Med. 23, 1–10 (2017).
Yuan, S., Norgard, R. J. & Stanger, B. Z. Cellular plasticity in cancer. Cancer Discov. 9, 837–851 (2019).
Boumahdi, S. & de Sauvage, F. J. The great escape: tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Discov. 19, 39–56 (2020).
Lugassy, C., Kleinman, H. K., Vermeulen, P. B. & Barnhill, R. L. Angiotropism, pericytic mimicry and extravascular migratory metastasis: an embryogenesis-derived program of tumor spread. Angiogenesis 23, 27–41 (2020).
Kuol, N., Stojanovska, L., Apostolopoulos, V. & Nurgali, K. Role of the nervous system in cancer metastasis. J. Exp. Clin. Cancer Res. 37, 5 (2018).
Yu, M. et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584 (2013).
Gkountela, S. et al. Circulating tumor cell clustering shapes DNA methylation to enable metastasis seeding. Cell 176, 98–112 (2019).
Pantel, K. & Speicher, M. R. The biology of circulating tumor cells. Oncogene 35, 1216–1224 (2016).
Micalizzi, D. S., Maheswaran, S. & Haber, D. A. A conduit to metastasis: circulating tumor cell biology. Genes Dev. 31, 1827–1840 (2017).
Fidler, I. J. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur. J. Cancer 9, 223–227 (1973).
Aceto, N., Toner, M., Maheswaran, S. & Haber, D. A. En route to metastasis: circulating tumor cell clusters and epithelial-to-mesenchymal transition. Trends Cancer 1, 44–52 (2015).
Chemi, F. et al. Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse. Nat. Med. 25, 1534–1539 (2019).
Heller, G. et al. Circulating tumor cell number as a response measure of prolonged survival for metastatic castration-resistant prostate cancer: a comparison with prostate-specific antigen across five randomized phase III clinical trials. J. Clin. Oncol. 36, 572–580 (2018).
Alix-Panabieres, C., Schwarzenbach, H. & Pantel, K. Circulating tumor cells and circulating tumor DNA. Annu. Rev. Med. 63, 199–215 (2012).
Cristofanilli, M. et al. The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): international expert consensus paper. Crit. Rev. Oncol. Hematol. 134, 39–45 (2019).
Pantel, K., Hille, C. & Scher, H. I. Circulating tumor cells in prostate cancer: from discovery to clinical utility. Clin. Chem. 65, 87–99 (2019).
Parikh, A. R. et al. Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers. Nat. Med. 25, 1415–1421 (2019).
Sosa, M. S., Bragado, P. & Aguirre-Ghiso, J. A. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat. Rev. Cancer 14, 611–622 (2014).
Phan, T. G. & Croucher, P. I. The dormant cancer cell life cycle. Nat. Rev. Cancer 20, 398–411 (2020).
Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).
Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016).
Carlson, P. et al. Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy. Nat. Cell Biol. 21, 238–250 (2019).
David, C. J. & Massagué, J. Contextual determinants of TGFβ action in development, immunity and cancer. Nat. Rev. Mol. Cell Biol. 19, 419–435 (2018).
Bragado, P. et al. TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38ɑ/β signalling. Nat. Cell Biol. 15, 1351–1361 (2013).
Prunier, C., Baker, D., Ten Dijke, P. & Ritsma, L. TGF-β family signaling pathways in cellular dormancy. Trends Cancer 5, 66–78 (2019).
Pommier, A. et al. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science https://doi.org/10.1126/science.aao4908 (2018).
Pantel, K. et al. Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. Cancer Res. 51, 4712–4715 (1991).
Koebel, C. M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–907 (2007).
Eyob, H. et al. Inhibition of Ron kinase blocks conversion of micrometastases to overt metastases by boosting antitumor immunity. Cancer Discov. 3, 751–760 (2013).
Ali, F. R. & Lear, J. T. Melanoma in organ transplant recipients: incidence, outcomes and management considerations. J. Skin Cancer 2012, 404615 (2012).
Tikhonova, A. N., Lasry, A., Austin, R. & Aifantis, I. Cell-by-cell deconstruction of stem cell niches. Cell Stem Cell 27, 19–34 (2020).
Scadden, D. T. Nice neighborhood: emerging concepts of the stem cell niche. Cell 157, 41–50 (2014).
Plaks, V., Kong, N. & Werb, Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16, 225–238 (2015).
Mohme, M., Riethdorf, S. & Pantel, K. Circulating and disseminated tumour cells—mechanisms of immune surveillance and escape. Nat. Rev. Clin. Oncol. 14, 155–167 (2017).
Garner, H. & de Visser, K. E. Immune crosstalk in cancer progression and metastatic spread: a complex conversation. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-019-0271-z (2020).
Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
Eyles, J. et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J. Clin. Invest. 120, 2030–2039 (2010).
Bidwell, B. N. et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat. Med. 18, 1224–1231 (2012).
Van den Eynde, M. et al. The link between the multiverse of immune microenvironments in metastases and the survival of colorectal cancer patients. Cancer Cell 34, 1012–1026 (2018).
Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).
Zheng, H. et al. Therapeutic antibody targeting tumor- and osteoblastic niche-derived Jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell 32, 731–747 (2017).
Zhang, J. et al. Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. J. Clin. Invest. 107, 1235–1244 (2001).
Chen, Q., Zhang, X. H. & Massagué, J. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20, 538–549 (2011).
Acharyya, S. et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012).
Albrengues, J. et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science https://doi.org/10.1126/science.aao4227 (2018).
Teijeira, A. et al. CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity 52, 856–871 (2020).
Ombrato, L. et al. Metastatic-niche labelling reveals parenchymal cells with stem features. Nature 572, 603–608 (2019).
Chen, Q. et al. Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533, 493–498 (2016).
Sevenich, L. et al. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat. Cell Biol. 16, 876–888 (2014).
Zeng, Q. et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature 573, 526–531 (2019).
Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).
Peinado, H. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat. Rev. Cancer 17, 302–317 (2017).
Fontebasso, Y. & Dubinett, S. M. Drug development for metastasis prevention. Crit. Rev. Oncog. 20, 449–473 (2015).
Risson, E., Nobre, A. R., Maguer-Satta, V. & Aguirre-Ghiso, J. A. The current paradigm and challenges ahead for the dormancy of disseminated tumor cells. Nat. Cancer 1, 672–680 (2020).
Parsons, S., Maldonado, E. B. & Prasad, V. Comparison of drugs used for adjuvant and metastatic therapy of colon, breast, and non-small cell lung cancers. JAMA Netw. Open 3, e202488 (2020).
Steeg, P. S. Perspective: The right trials. Nature 485, S58–59 (2012).
Vasan, N., Baselga, J. & Hyman, D. M. A view on drug resistance in cancer. Nature 575, 299–309 (2019).
Lito, P., Rosen, N. & Solit, D. B. Tumor adaptation and resistance to RAF inhibitors. Nat. Med. 19, 1401–1409 (2013).
Sabnis, A. J. & Bivona, T. G. Principles of resistance to targeted cancer therapy: lessons from basic and translational cancer biology. Trends Mol. Med. 25, 185–197 (2019).
Wu, Y.-L. et al. CTONG1104: adjuvant gefitinib versus chemotherapy for resected N1-N2 NSCLC with EGFR mutation—final overall survival analysis of the randomized phase III trial 1 analysis of the randomized phase III trial. J. Clin. Oncol. 38, 9005 (2020).
Jassem, J. Adjuvant EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: still an investigational approach. Transl. Lung Cancer Res. 8, S387–S390 (2019).
Mok, T. S. et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376, 629–640 (2017).
Herbst, R. S. et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J. Clin. Oncol. 38, abstract LBA5 (2020).
Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018).
Mateo, J. et al. A decade of clinical development of PARP inhibitors in perspective. Ann. Oncol. 30, 1437–1447 (2019).
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
Spring, L. M. et al. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet 395, 817–827 (2020).
Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8, 98–101 (1989).
Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
Haibe, Y. et al. Resistance mechanisms to anti-angiogenic therapies in cancer. Front. Oncol. 10, 221 (2020).
Iheanacho, K. & Vaishampayan, U. Perioperative approaches to kidney cancer. Clin. Adv. Hematol. Oncol. 18, 56–65 (2020).
Allegra, C. J. et al. Bevacizumab in stage II–III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J. Clin. Oncol. 31, 359–364 (2013).
Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).
Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019).
Haslam, A., Gill, J. & Prasad, V. Estimation of the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs. JAMA Netw. Open 3, e200423 (2020).
Hellmann, M. D. et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 18, 31–41 (2017).
Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
Long, G. V. et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 19, 672–681 (2018).
Schumacher, T. N., Scheper, W. & Kvistborg, P. Cancer neoantigens. Annu. Rev. Immunol. 37, 173–200 (2019).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).
Marabelle, A. et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 Study. J. Clin. Oncol. 38, 1–10 (2020).
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).
Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
Makker, V. et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 20, 711–718 (2019).
Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).
Fukuoka, S. et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603). J. Clin. Oncol. 38, 2053–2061 (2020).
Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378, 1789–1801 (2018).
Weber, J. et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 377, 1824–1835 (2017).
Eggermont, A. M. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375, 1845–1855 (2016).
Zimmer, L. et al. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 395, 1558–1568 (2020).
Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016).
Versluis, J. M., Long, G. V. & Blank, C. U. Learning from clinical trials of neoadjuvant checkpoint blockade. Nat. Med. 26, 475–484 (2020).
Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018).
Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018).
Forde, P. M. et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 378, 1976–1986 (2018).
Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723 (2017).
Creasy, J. M. et al. Actual 10-year survival after hepatic resection of colorectal liver metastases: what factors preclude cure? Surgery 163, 1238–1244 (2018).
Clark, M. E. & Smith, R. R. Liver-directed therapies in metastatic colorectal cancer. J. Gastrointest. Oncol. 5, 374–387 (2014).
Gomez, D. R. et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J. Clin. Oncol. 37, 1558–1565 (2019).
Palma, D. A. et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet 393, 2051–2058 (2019).
Parker, C. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N. Engl. J. Med. 369, 213–223 (2013).
Early Breast Cancer Trialists’ Collaborative Group. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 386, 1353–1361 (2015).
O’Carrigan, B. et al. Bisphosphonates and other bone agents for breast cancer. Cochrane Database of Systematic Reviews https://doi.org/10.1002/14651858.CD003474.pub4 (2017).
Lin, X. & DeAngelis, L. M. Treatment of brain metastases. J. Clin. Oncol. 33, 3475–3484 (2015).
Auperin, A. et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N. Engl. J. Med. 341, 476–484 (1999).
Boire, A. et al. Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis. Cell 168, 1101–1113 (2017).
Haro, M. A., Dyevoich, A. M., Phipps, J. P. & Haas, K. M. Activation of B-1 cells promotes tumor cell killing in the peritoneal cavity. Cancer Res. 79, 159–170 (2019).
Priego, N. et al. STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nat. Med. 24, 1024–1035 (2018).
Chi, Y. et al. Cancer cells deploy lipocalin-2 to collect limiting iron in leptomeningeal metastasis. Science 369, 276–282 (2020).
Suva, M. L. & Tirosh, I. Single-cell RNA sequencing in cancer: lessons learned and emerging challenges. Mol. Cell 75, 7–12 (2019).
Rozenblatt-Rosen, O. et al. The Human Tumor Atlas Network: charting tumor transitions across space and time at single-cell resolution. Cell 181, 236–249 (2020).
Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41–45 (2017).
Rekhtman, N. et al. Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin. Cancer Res. 22, 3618–3629 (2016).
Hamilton, K. et al. Prevalence and prognostic significance of neuroendocrine cells in esophageal adenocarcinoma. Mod. Pathol. 13, 475–481 (2000).
Adams, E. J. et al. FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes. Nature 571, 408–412 (2019).
Kaur, J., Daoud, A. & Eblen, S. T. Targeting chromatin remodeling for cancer therapy. Curr. Mol. Pharm. 12, 215–229 (2019).
Sparano, J. A. et al. Clinical and genomic risk to guide the use of adjuvant therapy for breast cancer. N. Engl. J. Med. 380, 2395–2405 (2019).
Sobrero, A. F. et al. Overall survival (OS) and long-term disease-free survival (DFS) of three versus six months of adjuvant (adj) oxaliplatin and fluoropyrimidine-based therapy for patients (pts) with stage III colon cancer (CC): final results from the IDEA (International Duration Evaluation of Adj chemotherapy) collaboration. J. Clin. Oncol. 38, 4004–4004 (2020).
Grothey, A. et al. Duration of adjuvant chemotherapy for stage III colon cancer. N. Engl. J. Med. 378, 1177–1188 (2018).
Coakley, M., Garcia-Murillas, I. & Turner, N. C. Molecular residual disease and adjuvant trial design in solid tumors. Clin. Cancer Res. 25, 6026–6034 (2019).
Pantel, K. & Alix-Panabières, C. Liquid biopsy and minimal residual disease—latest advances and implications for cure. Nat. Rev. Clin. Oncol. 16, 409–424 (2019).
Phallen, J. et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aan2415 (2017).
Cohen, J. D. et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 359, 926–930 (2018).
Razavi, P. et al. High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants. Nat. Med. 25, 1928–1937 (2019).
Helmink, B. A., Khan, M. A. W., Hermann, A., Gopalakrishnan, V. & Wargo, J. A. The microbiome, cancer, and cancer therapy. Nat. Med. 25, 377–388 (2019).
Geller, L. T. et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357, 1156–1160 (2017).
Nejman, D. et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368, 973–980 (2020).
Bullman, S. et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science 358, 1443–1448 (2017).
Parhi, L. et al. Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression. Nat. Commun. 11, 3259 (2020).
Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).
Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).
Forbes, N. S. et al. White paper on microbial anti-cancer therapy and prevention. J. Immunother. Cancer 6, 78 (2018).
Tuveson, D. & Clevers, H. Cancer modeling meets human organoid technology. Science 364, 952–955 (2019).
Vlachogiannis, G. et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 359, 920–926 (2018).
Ganesh, K. et al. A rectal cancer organoid platform to study individual responses to chemoradiation. Nat. Med. 25, 1607–1614 (2019).
Hapach, L. A., Mosier, J. A., Wang, W. & Reinhart-King, C. A. Engineered models to parse apart the metastatic cascade. NPJ Precis Oncol. 3, 20 (2019).
Yuki, K., Cheng, N., Nakano, M. & Kuo, C. J. Organoid models of tumor immunology. Trends Immunol. https://doi.org/10.1016/j.it.2020.06.010 (2020).
De La Rochere, P. et al. Humanized mice for the study of immuno-oncology. Trends Immunol. 39, 748–763 (2018).
Priestley, P. et al. Pan-cancer whole-genome analyses of metastatic solid tumours. Nature 575, 210–216 (2019).
Balachandran, V. P. et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516 (2017).
Iyer, G. et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 338, 221 (2012).
Doebele, R. C. et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol. 21, 271–282 (2020).
Prahallad, A. et al. Unresponsiveness of colon cancer to BRAFV600E inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).
Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).
The authors’ work in the subject area of this Review is supported by NIH grants R35CA252978 (J.M.), K08CA23021 (K.G.), P30-CA008748 (MSKCC) and the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center at MSKCC (J.M.).
J.M. owns stock of Scholar Rock, Inc. J.M. is an inventor on the following patents and patent applications: Assay for anti-metastatic agents (inventors: J.M. and L. Norton; no. 7,829,066; issued 9 November 2010), S100A8/A9 as a diagnostic marker and a therapeutic agent (inventor: J.M.; no. 2,831,593; granted 30 June 2018), Inhibiting cancer metastasis (inventors: J.M. and M. Valiente Cortes; no. 3,047,039; granted 31 July 2019), Methods for treating brain metastasis (inventors: J.M., Q. Chen and A. Boire; no. 10,413,522; issued 17 September 2019), Modulating permeability of the blood cerebrospinal fluid barrier (inventors: J.M. and A. A. Boire; application no. PCT/US2016/062880; published 18 November 2016). K.G. and J.M. are inventors on the following patent application: Treating metastatic cancer and model systems for metastatic disease (inventors: J.M., M. Valiente Cortes and K.G.; application no. PCT/US2017/045145; published 2 August 2017).
Peer review information Hannah Stower was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Ganesh, K., Massagué, J. Targeting metastatic cancer. Nat Med 27, 34–44 (2021). https://doi.org/10.1038/s41591-020-01195-4