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Emerging strategies for treating metastasis

Nature Cancer volume 2, pages 258–270 (2021)Cite this article

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Abstract

The systemic spread of tumor cells is the ultimate cause of the majority of deaths from cancer, yet few successful therapeutic strategies have emerged to specifically target metastasis. Here we discuss recent advances in our understanding of tumor-intrinsic pathways driving metastatic colonization and therapeutic resistance, as well as immune-activating strategies to target metastatic disease. We focus on therapeutically exploitable mechanisms, promising strategies in preclinical and clinical development, and emerging areas with potential to become innovative treatments.

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Fig. 1: Five-year survival rates of patients diagnosed with select cancer types in the time period from 2000–2017.
Fig. 2: Metastatic ability, therapeutic resistance and plasticity are intrinsically linked by genetic, epigenetic and metabolic pathways that offer promising therapeutic nodes for drug development.
Fig. 3: Development of metastasis competency requires additional malignant properties beyond primary tumorigenesis.
Fig. 4: Targeting the immune microenvironment of metastatic cancers.

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Data availability

The human cancer mortality data in Fig. 1 were derived from the SEER database with 2017 as the most recently annotated 5-year survival date: https://seer.cancer.gov/data/. Source data are provided with this paper. All other data are available from the corresponding author on reasonable request.

References

  1. Chaffer, C. L. & Weinberg, R. A. A perspective on cancer cell metastasis. Science 331, 1559–1564 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).

    Article  PubMed  Google Scholar 

  3. Ma, B., Wells, A. & Clark, A. M. The pan-therapeutic resistance of disseminated tumor cells: role of phenotypic plasticity and the metastatic microenvironment. Semin. Cancer Biol. 60, 138–147 (2020).

    Article  PubMed  Google Scholar 

  4. Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8, 1069–1086 (2018).

    Article  PubMed  Google Scholar 

  5. Litwin, M. S. & Tan, H. J. The diagnosis and treatment of prostate cancer: a review. JAMA 317, 2532–2542 (2017).

    Article  PubMed  Google Scholar 

  6. Kang, Y. & Pantel, K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell 23, 573–581 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sun, M. et al. Age-adjusted incidence, mortality, and survival rates of stage-specific renal cell carcinoma in North America: a trend analysis. Eur. Urol. 59, 135–141 (2011).

    Article  PubMed  Google Scholar 

  8. Eloubeidi, M. Temporal trends (1973–1997) in survival of patients with esophageal adenocarcinoma in the United States: a glimmer of hope? Am. J. Gastroenterol. 98, 1627–1633 (2003).

    Article  PubMed  Google Scholar 

  9. Brenner, H., Gondos, A. & Arndt, V. Recent major progress in long-term cancer patient survival disclosed by modeled period analysis. J. Clin. Oncol. 25, 3274–3280 (2007).

    Article  PubMed  Google Scholar 

  10. Peto, R. et al. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case–control studies. BMJ 321, 323–329 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lowy, D. R. & Schiller, J. T. Reducing HPV-associated cancer globally. Cancer Prev. Res. 5, 18–23 (2012).

    Article  Google Scholar 

  12. Clouston, S. A. P. et al. Fundamental causes of accelerated declines in colorectal cancer mortality: modeling multiple ways that disadvantage influences mortality risk. Soc. Sci. Med. 187, 1–10 (2017).

    Article  PubMed  Google Scholar 

  13. Davies, C. et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381, 805–816 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Riihimaki, M., Hemminki, A., Sundquist, J. & Hemminki, K. Patterns of metastasis in colon and rectal cancer. Sci. Rep. 6, 29765 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Hagemeister, F. B. Jr., Buzdar, A. U., Luna, M. A. & Blumenschein, G. R. Causes of death in breast cancer: a clinicopathologic study. Cancer 46, 162–167 (1980).

    Article  PubMed  Google Scholar 

  16. Nichols, L., Saunders, R. & Knollmann, F. D. Causes of death of patients with lung cancer. Arch. Pathol. Lab. Med. 136, 1552–1557 (2012).

    Article  PubMed  Google Scholar 

  17. Talmadge, J. E. & Fidler, I. J. AACR Centennial Series: The biology of cancer metastasis: historical perspective. Cancer Res. 70, 5649–5669 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hosseini, H. et al. Early dissemination seeds metastasis in breast cancer. Nature 540, 552–558 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Walling, H. W., Fosko, S. W., Geraminejad, P. A., Whitaker, D. C. & Arpey, C. J. Aggressive basal cell carcinoma: presentation, pathogenesis, and management. Cancer Metastasis Rev. 23, 389–402 (2004).

    Article  PubMed  Google Scholar 

  20. Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Weigelt, B., Peterse, J. L. & van ‘t Veer, L. J. Breast cancer metastasis: markers and models. Nat. Rev. Cancer 5, 591–602 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Roudier, M. P. et al. Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone. Hum. Pathol. 34, 646–653 (2003).

    Article  PubMed  Google Scholar 

  24. Brastianos, P. K. et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 5, 1164–1177 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hu, Z. et al. Quantitative evidence for early metastatic seeding in colorectal cancer. Nat. Genet. 51, 1113–1122 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Riethmuller, G. & Klein, C. A. Early cancer cell dissemination and late metastatic relapse: clinical reflections and biological approaches to the dormancy problem in patients. Semin. Cancer Biol. 11, 307–311 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. van de Wouw, A. J., Janssen-Heijnen, M. L., Coebergh, J. W. & Hillen, H. F. Epidemiology of unknown primary tumours; incidence and population-based survival of 1285 patients in southeast Netherlands, 1984–1992. Eur. J. Cancer 38, 409–413 (2002).

    Article  PubMed  Google Scholar 

  28. Jorgensen, K. J., Zahl, P. H. & Gotzsche, P. C. Breast cancer mortality in organised mammography screening in Denmark: comparative study. BMJ 340, c1241 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Barry, M. J. Screening for prostate cancer—the controversy that refuses to die. N. Engl. J. Med. 360, 1351–1354 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Lichtenberg, F. R. Has medical innovation reduced cancer mortality? CESifo Econ. Stud. 60, 135–177 (2013).

    Article  Google Scholar 

  31. Cutler, D. M. Are we finally winning the war on cancer? J. Econ. Perspect. 22, 3–26 (2008).

    Article  PubMed  Google Scholar 

  32. Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Smith, M. R. et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N. Engl. J. Med. 378, 1408–1418 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Arriagada, R. et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N. Engl. J. Med. 350, 351–360 (2004).

    Article  PubMed  Google Scholar 

  35. Group, Q. C. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 370, 2020–2029 (2007).

    Article  CAS  Google Scholar 

  36. Long, G. V. et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N. Engl. J. Med. 377, 1813–1823 (2017).

    Article  CAS  PubMed  Google Scholar 

  37. Brufsky, A. & Mathew, A. Bisphosphonates, bone, and breast cancer recurrence. Lancet 386, 1319–1320 (2015).

    Article  PubMed  Google Scholar 

  38. Guarneri, V., Barbieri, E., Dieci, M. V., Piacentini, F. & Conte, P. Anti-HER2 neoadjuvant and adjuvant therapies in HER2 positive breast cancer. Cancer Treat. Rev. 36, S62–S66 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Anderson, R. L. et al. A framework for the development of effective anti-metastatic agents. Nat. Rev. Clin. Oncol. 16, 185–204 (2019).

    Article  PubMed  Google Scholar 

  40. Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 17, 917–927 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365, 1687–1717 (2005).

  42. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAFV600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tan, A. C., Itchins, M. & Khasraw, M. Brain metastases in lung cancers with emerging targetable fusion drivers. Int. J. Mol. Sci. 21, 1416 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  44. Grothey, A. et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381, 303–312 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Van Cutsem, E. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009).

    Article  PubMed  Google Scholar 

  46. Andreopoulou, E. & Sparano, J. A. Chemotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer: an overview. Curr. Breast Cancer Rep. 5, 42–50 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lambert, J. M. & Chari, R. V. Ado-trastuzumab emtansine (T-DM1): an antibody–drug conjugate (ADC) for HER2-positive breast cancer. J. Med. Chem. 57, 6949–6964 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Bardia, A. et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N. Engl. J. Med. 380, 741–751 (2019).

    Article  CAS  PubMed  Google Scholar 

  49. Nagayama, A., Ellisen, L. W., Chabner, B. & Bardia, A. Antibody–drug conjugates for the treatment of solid tumors: clinical experience and latest developments. Target. Oncol. 12, 719–739 (2017).

    Article  PubMed  Google Scholar 

  50. Hess, L. M., Brnabic, A., Mason, O., Lee, P. & Barker, S. Relationship between progression-free survival and overall survival in randomized clinical trials of targeted and biologic agents in oncology. J. Cancer 10, 3717–3727 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vandenbroucke, R. E. & Libert, C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat. Rev. Drug Discov. 13, 904–927 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Lindemann, F., Schlimok, G., Dirschedl, P., Witte, J. & Riethmuller, G. Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients. Lancet 340, 685–689 (1992).

    Article  CAS  PubMed  Google Scholar 

  55. Hüsemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008).

    Article  PubMed  CAS  Google Scholar 

  56. Melchior, S. W. et al. Early tumor cell dissemination in patients with clinically localized carcinoma of the prostate. Clin. Cancer Res. 3, 249–256 (1997).

    CAS  PubMed  Google Scholar 

  57. Davis, B. W. et al. Prognostic significance of tumor grade in clinical trials of adjuvant therapy for breast cancer with axillary lymph node metastasis. Cancer 58, 2662–2670 (1986).

    Article  CAS  PubMed  Google Scholar 

  58. Scheel, C. & Weinberg, R. A. Cancer stem cells and epithelial–mesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22, 396–403 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yang, J. et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 21, 341–352 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Fischer, K. R. et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shackleton, M., Quintana, E., Fearon, E. R. & Morrison, S. J. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138, 822–829 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Quintana, E. et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jaggupilli, A. & Elkord, E. Significance of CD44 and CD24 as cancer stem cell markers: an enduring ambiguity. Clin. Dev. Immunol. 2012, 708036 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Auffinger, B. et al. Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy. Cell Death Differ. 21, 1119–1131 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Todaro, M. et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1, 389–402 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Yu, M. et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Domingo-Domenech, J. et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of Notch- and Hedgehog-dependent tumor-initiating cells. Cancer Cell 22, 373–388 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kerbel, R. S., Kobayashi, H. & Graham, C. H. Intrinsic or acquired drug resistance and metastasis: are they linked phenotypes? J. Cell. Biochem. 56, 37–47 (1994).

    Article  CAS  PubMed  Google Scholar 

  71. Hu, G. et al. MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell 15, 9–20 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wan, L. et al. MTDH–SND1 interaction is crucial for expansion and activity of tumor-initiating cells in diverse oncogene- and carcinogen-induced mammary tumors. Cancer Cell 26, 92–105 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Takebe, N., Harris, P. J., Warren, R. Q. & Ivy, S. P. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat. Rev. Clin. Oncol. 8, 97–106 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Takebe, N. et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat. Rev. Clin. Oncol. 12, 445–464 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chakrabarti, R. et al. Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche. Science 360, eaan4153 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. McAuliffe, S. M. et al. Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. Proc. Natl Acad. Sci. USA 109, E2939–E2948 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zayzafoon, M., Abdulkadir, S. A. & McDonald, J. M. Notch signaling and ERK activation are important for the osteomimetic properties of prostate cancer bone metastatic cell lines. J. Biol. Chem. 279, 3662–3670 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Sun, L. et al. Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes. Nat. Cell Biol. 21, 1015–1026 (2019).

    Article  CAS  PubMed  Google Scholar 

  79. Xing, F. et al. Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain. EMBO Mol. Med. 5, 384–396 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sethi, N., Dai, X., Winter, C. G. & Kang, Y. Tumor-derived Jagged1 promotes osteolytic bone metastasis of breast cancer by engaging Notch signaling in bone cells. Cancer Cell 19, 192–205 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yen, W. C. et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin. Cancer Res. 21, 2084–2095 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Wu, C. X. et al. Notch inhibitor PF-03084014 inhibits hepatocellular carcinoma growth and metastasis via suppression of cancer stemness due to reduced activation of Notch1–Stat3. Mol. Cancer Ther. 16, 1531–1543 (2017).

    Article  CAS  PubMed  Google Scholar 

  83. Zheng, H. et al. Therapeutic antibody targeting tumor- and osteoblastic niche-derived Jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell 32, 731–747 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Shih, I.-M. & Wang, T. L. Notch signaling, γ-secretase inhibitors, and cancer therapy. Cancer Res. 67, 1879–1882 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. McKeage, M. J. et al. Phase IB trial of the anti-cancer stem cell DLL4-binding agent demcizumab with pemetrexed and carboplatin as first-line treatment of metastatic non-squamous NSCLC. Target. Oncol. 13, 89–98 (2018).

    Article  PubMed  Google Scholar 

  86. Hu, Z. I. et al. A randomized phase II trial of nab-paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer. Cancer Med. 8, 5148–5157 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Marcucci, F., Caserta, C. A., Romeo, E. & Rumio, C. Antibody–drug conjugates (ADC) against cancer stem-like cells (CSC)—is there still room for optimism? Front. Oncol. 9, 167 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Kummar, S. et al. Clinical activity of the γ-secretase inhibitor PF-03084014 in adults with desmoid tumors (aggressive fibromatosis). J. Clin. Oncol. 35, 1561–1569 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Anastas, J. N. & Moon, R. T. WNT signalling pathways as therapeutic targets in cancer. Nat. Rev. Cancer 13, 11–26 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Kemper, K. et al. Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells. Stem Cells 30, 2378–2386 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Lee, S. H. et al. Wnt/β-catenin signalling maintains self-renewal and tumourigenicity of head and neck squamous cell carcinoma stem-like cells by activating Oct4. J. Pathol. 234, 99–107 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. DiMeo, T. A. et al. A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial–mesenchymal transition in basal-like breast cancer. Cancer Res. 69, 5364–5373 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Esposito, M. et al. Bone vascular niche E-selectin induces mesenchymal–epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat. Cell Biol. 21, 627–639 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhuang, X. et al. Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1. Nat. Cell Biol. 19, 1274–1285 (2017).

    Article  CAS  PubMed  Google Scholar 

  96. Moore, K. N. et al. A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer. Gynecol. Oncol. 154, 294–301 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Davis, S. L. et al. A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer. Invest. New Drugs 38, 821–830 (2020).

    Article  CAS  PubMed  Google Scholar 

  98. Ren, D. N. et al. LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis. Nat. Commun. 6, 6906 (2015).

    Article  PubMed  CAS  Google Scholar 

  99. Massague, J. TGFβ signalling in context. Nat. Rev. Mol. Cell Biol. 13, 616–630 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Takaku, K. et al. Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell 92, 645–656 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. Celia-Terrassa, T. et al. Hysteresis control of epithelial–mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability. Nat. Commun. 9, 5005 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Calon, A. et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Padua, D. et al. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66–77 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Bandyopadhyay, A. et al. Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-β type I receptor kinase inhibitor. Cancer Res. 66, 6714–6721 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Esposito, M., Guise, T. & Kang, Y. The biology of bone metastasis. Cold Spring Harb. Perspect. Med. 8, a031252 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Colak, S. & Ten Dijke, P. Targeting TGF-β signaling in cancer. Trends Cancer 3, 56–71 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. Morris, J. C. et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-β (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS ONE 9, e90353 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Ruiz i Altaba, A. Hedgehog signaling and the Gli code in stem cells, cancer, and metastases. Sci. Signal. 4, pt9 (2011).

    PubMed  Google Scholar 

  110. Yauch, R. L. et al. A paracrine requirement for Hedgehog signalling in cancer. Nature 455, 406–410 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Sterling, J. A. et al. The Hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells. Cancer Res. 66, 7548–7553 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Feldmann, G. et al. An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol. Cancer Ther. 7, 2725–2735 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sekulic, A. et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer 17, 332 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Lee, J. J. et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091–E3100 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pastushenko, I. et al. Identification of the tumour transition states occurring during EMT. Nature 556, 463–468 (2018).

    Article  CAS  PubMed  Google Scholar 

  116. Su, Y. et al. Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance. Proc. Natl Acad. Sci. USA 114, 13679–13684 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yuan, S. et al. Global regulation of the histone mark H3K36me2 underlies epithelial plasticity and metastatic progression. Cancer Discov. 10, 854–871 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Brabletz, T. et al. Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc. Natl Acad. Sci. USA 98, 10356–10361 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial–mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jabbour, E., Issa, J. P., Garcia-Manero, G. & Kantarjian, H. Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer 112, 2341–2351 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Richter, G. H. et al. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. Proc. Natl Acad. Sci. USA 106, 5324–5329 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Zingg, D. et al. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nat. Commun. 6, 6051 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Ku, S. Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78–83 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Italiano, A. et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 19, 649–659 (2018).

    Article  CAS  PubMed  Google Scholar 

  128. Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet. 37, 391–400 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Yardley, D. A. et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J. Clin. Oncol. 31, 2128–2135 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Jiang, Z. et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 20, 806–815 (2019).

    Article  CAS  PubMed  Google Scholar 

  131. Schech, A., Kazi, A., Yu, S., Shah, P. & Sabnis, G. Histone deacetylase inhibitor entinostat inhibits tumor-initiating cells in triple-negative breast cancer cells. Mol. Cancer Ther. 14, 1848–1857 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Vanharanta, S. & Massague, J. Origins of metastatic traits. Cancer Cell 24, 410–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 173, 371–385 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Bakhoum, S. F. et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553, 467–472 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Frankowski, K. J. et al. Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis. Sci. Transl. Med. 10, eaap8307 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Gupta, G. P. & Massague, J. Cancer metastasis: building a framework. Cell 127, 679–695 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Shimizu, T. et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin. Cancer Res. 18, 2316–2325 (2012).

    Article  CAS  PubMed  Google Scholar 

  138. Banerjee, S. N. & Lord, C. J. First-line PARP inhibition in ovarian cancer—standard of care for all? Nat. Rev. Clin. Oncol. 17, 136–137 (2020).

    Article  CAS  PubMed  Google Scholar 

  139. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Jung, A. Y. et al. Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy. Am. J. Clin. Nutr. 109, 69–78 (2019).

    Article  PubMed  Google Scholar 

  141. Gill, J. G., Piskounova, E. & Morrison, S. J. Cancer, oxidative stress, and metastasis. Cold Spring Harb. Symp. Quant. Biol. 81, 163–175 (2016).

    Article  PubMed  Google Scholar 

  142. Ambrosone, C. B. et al. Dietary supplement use during chemotherapy and survival outcomes of patients with breast cancer enrolled in a cooperative group clinical trial (SWOG S0221). J. Clin. Oncol. 38, 804–814 (2020).

    Article  CAS  PubMed  Google Scholar 

  143. Breau, M. et al. The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in mice. JCI Insight 4, e127647 (2019).

    Article  PubMed Central  Google Scholar 

  144. Sayin, V. I. et al. Antioxidants accelerate lung cancer progression in mice. Sci. Transl. Med. 6, 221ra215 (2014).

    Article  CAS  Google Scholar 

  145. Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186–191 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Tasdogan, A. et al. Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 577, 115–120 (2020).

    Article  CAS  PubMed  Google Scholar 

  147. Silva, M. M., Rocha, C. R. R., Kinker, G. S., Pelegrini, A. L. & Menck, C. F. M. The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells. Sci. Rep. 9, 17639 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Ramanathan, B. et al. Resistance to paclitaxel is proportional to cellular total antioxidant capacity. Cancer Res. 65, 8455–8460 (2005).

    Article  CAS  PubMed  Google Scholar 

  149. Ghergurovich, J. M. et al. Glucose-6-phosphate dehydrogenase is not essential for K-Ras-driven tumor growth or metastasis. Cancer Res. 80, 3820–3829 (2020).

  150. Zhang, Y. et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat. Cell Biol. 20, 1181–1192 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Pani, G., Galeotti, T. & Chiarugi, P. Metastasis: cancer cell’s escape from oxidative stress. Cancer Metastasis Rev. 29, 351–378 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Harris, I. S. et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27, 211–222 (2015).

    Article  CAS  PubMed  Google Scholar 

  153. Wiel, C. et al. BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell 178, 330–345 (2019).

    Article  CAS  PubMed  Google Scholar 

  154. Cuadrado, A. et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 18, 295–317 (2019).

    Article  CAS  PubMed  Google Scholar 

  155. Wang, X. J. et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29, 1235–1243 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Ginestier, C. et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1, 555–567 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Koppaka, V. et al. Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol. Rev. 64, 520–539 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Marcato, P. et al. Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem Cells 29, 32–45 (2011).

    Article  CAS  PubMed  Google Scholar 

  159. Luo, Y. et al. ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets. Stem Cells 30, 2100–2113 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Wu, W. et al. Lipid peroxidation plays an important role in chemotherapeutic effects of temozolomide and the development of therapy resistance in human glioblastoma. Transl. Oncol. 13, 100748 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Ducker, G. S. et al. Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway. Cell Metab. 24, 640–641 (2016).

    Article  CAS  PubMed  Google Scholar 

  162. van Weverwijk, A. et al. Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation. Nat. Commun. 10, 2698 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Wang, Y. N. et al. CPT1A-mediated fatty acid oxidation promotes colorectal cancer cell metastasis by inhibiting anoikis. Oncogene 37, 6025–6040 (2018).

    Article  CAS  PubMed  Google Scholar 

  164. Young, R. M. et al. Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. Genes Dev. 27, 1115–1131 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41–45 (2017).

    Article  CAS  PubMed  Google Scholar 

  166. Staschke, K. A. & Wek, R. C. Adapting to cell stress from inside and out. Nat. Cell Biol. 21, 799–800 (2019).

    Article  CAS  PubMed  Google Scholar 

  167. Pommier, A. et al. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science 360, eaao4908 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Feng, Y. X. et al. Cancer-specific PERK signaling drives invasion and metastasis through CREB3L1. Nat. Commun. 8, 1079 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Thorburn, A., Thamm, D. H. & Gustafson, D. L. Autophagy and cancer therapy. Mol. Pharmacol. 85, 830–838 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Kalbasi, A. & Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 20, 25–39 (2020).

    Article  CAS  PubMed  Google Scholar 

  171. Qin, S. et al. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol. Cancer 18, 155 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923–937 (2014).

    Article  CAS  PubMed  Google Scholar 

  173. Ganesan, S. & Mehnert, J. Biomarkers for response to immune checkpoint blockade. Annu. Rev. Cancer Biol. 4, 331–351 (2020).

    Article  Google Scholar 

  174. Ramapriyan, R. et al. Altered cancer metabolism in mechanisms of immunotherapy resistance. Pharmacol. Ther. 195, 162–171 (2019).

    Article  CAS  PubMed  Google Scholar 

  175. Allard, D., Chrobak, P., Allard, B., Messaoudi, N. & Stagg, J. Targeting the CD73–adenosine axis in immuno-oncology. Immunol. Lett. 205, 31–39 (2019).

    Article  CAS  PubMed  Google Scholar 

  176. Gunther, J., Dabritz, J. & Wirthgen, E. Limitations and off-target effects of tryptophan-related IDO inhibitors in cancer treatment. Front. Immunol. 10, 1801 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Manzo, T. et al. Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells. J. Exp. Med. 217, e20191920 (2020).

  178. Wang, H. et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat. Immunol. 21, 298–308 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Sikic, B. I. et al. First-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J. Clin. Oncol. 37, 946–953 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Priceman, S. J. et al. Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2+ breast cancer metastasis to the brain. Clin. Cancer Res. 24, 95–105 (2018).

    Article  CAS  PubMed  Google Scholar 

  181. Newick, K., O’Brien, S., Moon, E. & Albelda, S. M. CAR T cell therapy for solid tumors. Annu. Rev. Med. 68, 139–152 (2017).

    Article  CAS  PubMed  Google Scholar 

  182. Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Chen, L. et al. Rejection of metastatic 4T1 breast cancer by attenuation of Treg cells in combination with immune stimulation. Mol. Ther. 15, 2194–2202 (2007).

    Article  CAS  PubMed  Google Scholar 

  184. Jang, J. E. et al. Crosstalk between regulatory T cells and tumor-associated dendritic cells negates anti-tumor immunity in pancreatic cancer. Cell Rep. 20, 558–571 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Marabelle, A. et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J. Clin. Invest. 123, 2447–2463 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. & Allison, J. P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206, 1717–1725 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Maldonado, R. A. & von Andrian, U. H. How tolerogenic dendritic cells induce regulatory T cells. Adv. Immunol. 108, 111–165 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Mucida, D. et al. Reciprocal TH17 ad regulatory T cell differnetiation mediated by retinoic acid. Science 317, 1958–1968 (2007).

    Article  CAS  Google Scholar 

  189. Galvin, K. C. et al. Blocking retinoic acid receptor-α enhances the efficacy of a dendritic cell vaccine against tumours by suppressing the induction of regulatory T cells. Cancer Immunol. Immunother. 62, 1273–1282 (2013).

    Article  CAS  PubMed  Google Scholar 

  190. Formenti, S. C. et al. Focal irradiation and systemic TGFβ blockade in metastatic breast cancer. Clin. Cancer Res. 24, 2493–2504 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Kelley, R. K. et al. A phase 2 study of galunisertib (TGF-β1 receptor type I inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma. Clin. Transl. Gastroenterol. 10, e00056 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Li, S. et al. Cancer immunotherapy via targeted TGF-β signalling blockade in TH cells. Nature 587, 121–125 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Lan, Y. et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci. Transl. Med. 10, eaan5488 (2018).

    Article  PubMed  CAS  Google Scholar 

  194. Rech, A. J. & Vonderheide, R. H. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann. N.Y. Acad. Sci. 1174, 99–106 (2009).

    Article  CAS  PubMed  Google Scholar 

  195. Dien, V. T., Morris, S. E., Karadeema, R. J. & Romesberg, F. E. Expansion of the genetic code via expansion of the genetic alphabet. Curr. Opin. Chem. Biol. 46, 196–202 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Hall, J. A., Grainger, J. R., Spencer, S. P. & Belkaid, Y. The role of retinoic acid in tolerance and immunity. Immunity 35, 13–22 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Devalaraja, S. et al. Tumor-derived retinoic acid regulates intratumoral monocyte differentiation to promote immune suppression. Cell 180, 1098–1114 (2020).

  198. Ruzicka, T. et al. Oral alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard therapy: results of a randomized, double-blind, placebo-controlled, multicenter trial. Arch. Dermatol. 140, 1453–1459 (2004).

    Article  CAS  PubMed  Google Scholar 

  199. Salvagno, C. et al. Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response. Nat. Cell Biol. 21, 511–521 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Georgoudaki, A. M. et al. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep. 15, 2000–2011 (2016).

    Article  CAS  PubMed  Google Scholar 

  201. Eyob, H. et al. Inhibition of Ron kinase blocks conversion of micrometastases to overt metastases by boosting antitumor immunity. Cancer Discovery 3, 751–760 (2013).

  202. Chen, J. et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell 19, 541–555 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Wu, H. et al. Lipid droplet-dependent fatty acid metabolism controls the immune suppressive phenotype of tumor-associated macrophages. EMBO Mol. Med. 11, e10698 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Quail, D. F. et al. Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF. Nat. Cell Biol. 19, 974–987 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Thibault, A. et al. A Phase II study of 5-AZA-2'deoxycytidine (decitabine) in hormone independent metastatic (D2) prostate cancer. Tumori J. 84, 87–89 (1998).

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Acknowledgements

We thank the members of our laboratory for helpful discussions. We also apologize to the many investigators whose important studies could not be cited directly here owing to space limitations. The work in the authors’ laboratories is supported by grants from the Brewster Foundation, the American Cancer Society, the Susan G. Komen Foundation, the Breast Cancer Research Foundation, the NIH and the US Department of Defense to Y.K. S.G. is supported by grants from the NCI, the US Department of Defense, the Breast Cancer Research Foundation, Hugs for Brady, AHEPA, the Val Skinner Foundation and the Gertrude Fogarty Trust.

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Authors and Affiliations

  1. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    Mark Esposito & Yibin Kang

  2. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Shridar Ganesan & Yibin Kang

  3. Center for Systems and Computational Biology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA

    Shridar Ganesan

  4. Department of Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA

    Shridar Ganesan

  5. Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA

    Yibin Kang

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Correspondence to Yibin Kang.

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Competing interests

M.E. holds equity interest and a management position in KayoThera, a company developing cancer therapeutics. Y.K. holds equity interest in KayoThera and Firebrand Therapeutics and is a member of the scientific advisory boards of KayoThera, Firebrand Therapeutics and Cytocares. Y.K. has consulted for Merck, Amgen and Ono Pharma and has previously received funding support from Merck, Amgen, Johnson & Johnson, Janssen, Glycomimetics and Ono Pharma. S.G. has consulted for Merck, Roche, Foundation Medicine, Foghorn Therapeutics, Novartis, Silagene, EQRX and Inspirata, has received research funding from M2GEN and has equity interest in Inspirata and Silagene.

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Fig. 1 5-year survival rates for the select cancers shown in Fig. 1 extracted from the SEER database (2020).

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Esposito, M., Ganesan, S. & Kang, Y. Emerging strategies for treating metastasis. Nat Cancer 2, 258–270 (2021). https://doi.org/10.1038/s43018-021-00181-0

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