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Oncofetal reprogramming in tumour development and progression

Abstract

Embryonic development is characterized by rapidly dividing cells, cellular plasticity and a highly vascular microenvironment. These features are similar to those of tumour tissue, in that malignant cells are characterized by their ability to proliferate and exhibit cellular plasticity. The tumour microenvironment also often includes immunosuppressive features. Reciprocal communication between various cellular subpopulations enables fetal and tumour tissues to proliferate, migrate and escape immune responses. Fetal-like reprogramming has been demonstrated in the tumour microenvironment, indicating extraordinary cellular plasticity and bringing an additional layer of cellular heterogeneity. More importantly, some of these features are also present during inflammation. This Perspective discusses the similarity between embryogenesis, inflammation and tumorigenesis, and describes the mechanisms of oncofetal reprogramming that enable tumour cells to escape from immune responses, promoting tumour growth and metastasis.

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Fig. 1: Similarities between embryogenesis, inflammation and tumorigenesis.
Fig. 2: Timeline of developments in the history of oncofetal reprogramming.
Fig. 3: Mechanism of oncofetal reprogramming.
Fig. 4: Oncofetal score as a predictor of treatment response.

References

  1. Ma, Y. et al. The relationship between early embryo development and tumourigenesis. J. Cell Mol. Med. 14, 2697–2701 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Manzo, G. Similarities between embryo development and cancer process suggest new strategies for research and therapy of tumors: a new point of view. Front. Cell Dev. Biol. 7, 20 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kerosuo, L. & Bronner-Fraser, M. What is bad in cancer is good in the embryo: importance of EMT in neural crest development. Semin. Cell Dev. Biol. 23, 320–332 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Caramel, J. et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 24, 466–480 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sharma, A. et al. Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in hepatocellular carcinoma. Cell 183, 377–394.e21 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. Lambrechts, D. et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24, 1277–1289 (2018).

    Article  CAS  PubMed  Google Scholar 

  10. Suvà, M. L. & Tirosh, I. Single-cell RNA sequencing in cancer: lessons learned and emerging challenges. Mol. Cell 75, 7–12 (2019).

    Article  PubMed  Google Scholar 

  11. Puram, S. V. et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 171, 1611–1624.e24 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Smith, E. A. & Hodges, H. C. The spatial and genomic hierarchy of tumor ecosystems revealed by single-cell technologies. Trends Cancer 5, 411–425 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ungefroren, H., Sebens, S., Seidl, D., Lehnert, H. & Hass, R. Interaction of tumor cells with the microenvironment. Cell Commun. Signal. 9, 18 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Flier, J. S., Underhill, L. H. & Dvorak, H. F. Tumors: wounds that do not heal. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  Google Scholar 

  17. Rodrigues, M., Kosaric, N., Bonham, C. A. & Gurtner, G. C. Wound healing: a cellular perspective. Physiol. Rev. 99, 665–706 (2019).

    Article  CAS  PubMed  Google Scholar 

  18. Deyell, M., Garris, C. S. & Laughney, A. M. Cancer metastasis as a non-healing wound. Br. J. Cancer 124, 1491–1502 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wynn, T. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199–210 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Hayashi, P. H. & Zeldis, J. B. Molecular biology of viral hepatitis and hepatocellular carcinoma. Compr. Ther. 19, 188–196 (1993).

    CAS  PubMed  Google Scholar 

  22. Pera, M. et al. Barrett’s disease: pathophysiology of metaplasia and adenocarcinoma. Ann. Thorac. Surg. 56, 1191–1197 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Bedwani, R. et al. Schistosomiasis and the risk of bladder cancer in Alexandria, Egypt. Br. J. Cancer 77, 1186–1189 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Choi, P. M. & Zelig, M. P. Similarity of colorectal cancer in Crohn’s disease and ulcerative colitis: implications for carcinogenesis and prevention. Gut 35, 950–954 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Toller, I. M. et al. Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells. Proc. Natl Acad. Sci. USA 108, 14944–14949 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Aguilar-Cazares, D. et al. Contribution of angiogenesis to inflammation and cancer. Front. Oncol. 9, 1399 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Yang, J. & Weinberg, R. A. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14, 818–829 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).

    Article  CAS  PubMed  Google Scholar 

  29. Brabletz, T., Kalluri, R., Nieto, M. A. & Weinberg, R. A. EMT in cancer. Nat. Rev. Cancer 18, 128–134 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Stone, R. C. et al. Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res. 365, 495–506 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yan, C. et al. Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-α through bone morphogenic protein-2. Am. J. Pathol. 176, 2247–2258 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Reynolds, G. et al. Developmental cell programs are co-opted in inflammatory skin disease. Science 371, eaba6500 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rosenblum, D. & Naik, S. New dog, old tricks: developmental programs resurface in inflammation. Cell Stem Cell 28, 592–594 (2021).

    Article  CAS  PubMed  Google Scholar 

  34. Zhu, X. et al. Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention. Signal. Transduct. Target. Ther. 6, 245 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kundu, J. K. & Surh, Y.-J. Inflammation: gearing the journey to cancer. Mutat. Res. 659, 15–30 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Lillie, F. R. The Development of the Chick: an Introduction to Embryology, 2nd edn. (Henry Holt, 1908).

  37. Abelev, G. I., Perova, S. D., Khramkova, N. I., Postnikova, Z. A. & Irlin, I. S. Production of embryonal α-globulin by transplantable mouse hepatomas. Transplantation 1, 174–180 (1963).

    Article  CAS  PubMed  Google Scholar 

  38. Gold, P. & Freedman, S. O. Specific carcinoembryonic antigens of the human digestive system. J. Exp. Med. 122, 467–481 (1965).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schapira, F., Dreyfus, J.-C. & Schapira, G. Anomaly of aldolase in primary liver cancer. Nature 200, 995–997 (1963).

    Article  CAS  PubMed  Google Scholar 

  40. Banwo, O., Versey, J. & Hobbs, J. R. New oncofetal antigen for human pancreas. Lancet 303, 643–645 (1974).

    Article  Google Scholar 

  41. Laurence, D. J. R. et al. Role of plasma carcinoembryonic antigen in diagnosis of gastrointestinal, mammary, and bronchial carcinoma. Br. Med. J. 3, 605–609 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Marchand, A., Fenoglio, C. M., Pascal, R., Richart, R. M. & Bennett, S. Carcinoembryonic antigen in human ovarian neoplasms. Cancer Res. 35, 3807–3810 (1975).

    CAS  PubMed  Google Scholar 

  43. Neufeld, L. et al. Carcinoembryonic antigen in the diagnosis of prostate carcinoma. Oncology 29, 376–381 (1974).

    Article  CAS  PubMed  Google Scholar 

  44. Trevisani, F., Garuti, F. & Neri, A. Alpha-fetoprotein for diagnosis, prognosis, and transplant selection. Semin. Liver Dis. 39, 163–177 (2019).

    Article  CAS  PubMed  Google Scholar 

  45. Galle, P. R. et al. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma. Liver Int. 39, 2214–2229 (2019).

    Article  PubMed  Google Scholar 

  46. McIntire, K. R., Waldmann, T. A., Moertel, C. G. & Go, V. L. Serum alpha-fetoprotein in patients with neoplasms of the gastrointestinal tract. Cancer Res. 35, 991–996 (1975).

    CAS  PubMed  Google Scholar 

  47. Kashala, L. O., Kalengayi, M. M. R. & Essex, M. Alpha-fetoprotein synthesis in human hepatocellular carcinoma: correlation with hepatitis B surface antigen expression. Cancer Invest. 10, 513–522 (2009).

    Article  Google Scholar 

  48. Abelev, G. I. Alpha-fetoprotein in ontogenesis and its association with malignant tumors. Adv. Cancer Res. 14, 295–358 (1971).

    Article  CAS  PubMed  Google Scholar 

  49. Ruoslahti, E. & Seppälä, M. Alpha-fetoprotein in cancer and fetal development. Adv. Cancer Res. 29, 275–346 (1979).

    Article  CAS  PubMed  Google Scholar 

  50. Taketa, K. α-fetoprotein: reevaluation in hepatology. Hepatology 12, 1420–1432 (1990).

    Article  CAS  PubMed  Google Scholar 

  51. Kew, M. Alpha-fetoprotein in primary liver cancer and other diseases. Gut 15, 814–821 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Borras, G., Molina, R., Xercavins, J., Ballesta, A. & Iglesias, J. Tumor antigens CA 19.9, CA 125, and CEA in carcinoma of the uterine cervix. Gynecol. Oncol. 57, 205–211 (1995).

    Article  CAS  PubMed  Google Scholar 

  53. Screaton, R. A., Penn, L. Z. & Stanners, C. P. Carcinoembryonic antigen, a human tumor marker, cooperates with Myc and Bcl-2 in cellular transformation. J. Cell Biol. 137, 939–952 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gold, P. & Goldenberg, N. A. The carcinoembryonic antigen (CEA): past, present, and future. McGill J. Med. 3, 46–66 (2020).

    Article  Google Scholar 

  55. Panidis, D., Vlassis, G., Matalliotakis, J., Skiadopoulos, S. & Kalogeropoulos, A. Serum levels of the oncofetal antigens CA-125, CA 19-9 and CA 15-3 in patients with endometriosis. J. Endocrinol. Invest. 11, 801–804 (1988).

    Article  CAS  PubMed  Google Scholar 

  56. Jäger, W., Kissing, A., Cilaci, S., Melsheimer, R. & Lang, N. Is an increase in CA 125 in breast cancer patients an indicator of pleural metastases? Br. J. Cancer 70, 493–495 (1994).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bast, R. C. et al. Reactivity of a monoclonal antibody with human ovarian carcinoma. J. Clin. Invest. 68, 1331–1337 (1981).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Jiang, T., Huang, L. & Zhang, S. Preoperative serum CA125: a useful marker for surgical management of endometrial cancer. BMC Cancer 15, 396 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Gardner, G. J. et al. CA125 regression in ovarian cancer patients treated with intravenous versus intraperitoneal platinum-based chemotherapy: a gynecologic oncology group study. Gynecol. Oncol. 124, 216–220 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Fawunmi, D., Gojon, H. & Valachis, A. The effectiveness of ovarian cancer screening in high-risk population and BRCA 1/2 carriers: a systematic review and meta-analysis. J. Clin. Oncol. 31, 1568–1568 (2013).

    Article  Google Scholar 

  61. May, T. et al. The prognostic value of perioperative, pre-systemic therapy CA125 levels in patients with high-grade serous ovarian cancer. Int. J. Gynecol. Obstet. 140, 247–252 (2018).

    Article  CAS  Google Scholar 

  62. Yong, K. J. et al. Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. N. Engl. J. Med. 368, 2266–2276 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bella, L., Zona, S., Moraes, G. Nde & Lam, E. W.-F. FOXM1: a key oncofoetal transcription factor in health and disease. Semin. Cancer Biol. 29, 32–39 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Müller, S. et al. The oncofetal RNA-binding protein IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression in cancer. Nucleic Acids Res. 48, 8576–8590 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Yu, Y. et al. Long non-coding RNA PVT1 promotes cell proliferation and migration by silencing ANGPTL4 expression in cholangiocarcinoma. Mol. Ther. Nucleic Acids 13, 503–513 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cheng, S.-W. et al. Lin28B is an oncofetal circulating cancer stem cell-like marker associated with recurrence of hepatocellular carcinoma. PLoS ONE 8, e80053 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Ramos, A. D. et al. Integration of genome-wide approaches identifies lncRNAs of adult neural stem cells and their progeny in vivo. Cell Stem Cell 12, 616–628 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ma, Y. et al. Elevated oncofoetal miR-17-5p expression regulates colorectal cancer progression by repressing its target gene P130. Nat. Commun. 3, 1291 (2012).

    Article  PubMed  Google Scholar 

  69. Ozaki, T. & Nakagawara, A. role of p53 in cell death and human cancers. Cancers 3, 994–1013 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Raveh, E., Matouk, I. J., Gilon, M. & Hochberg, A. The H19 long non-coding RNA in cancer initiation, progression and metastasis — a proposed unifying theory. Mol. Cancer 14, 184 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Liu, C. et al. H19-derived miR-675 contributes to bladder cancer cell proliferation by regulating p53 activation. Tumour Biol. 37, 263–270 (2015).

    Article  PubMed  Google Scholar 

  72. Yang, F. et al. Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J. 279, 3159–3165 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Carramusa, L. et al. The PVT-1 oncogene is a Myc protein target that is overexpressed in transformed cells. J. Cell Physiol. 213, 511–518 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Haverty, P. M., Hon, L. S., Kaminker, J. S., Chant, J. & Zhang, Z. High-resolution analysis of copy number alterations and associated expression changes in ovarian tumors. BMC Med. Genomics 2, 21 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Sircoulomb, F. et al. Genome profiling of ERBB2-amplified breast cancers. BMC Cancer 10, 539 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Kamath, A. et al. Double-minute MYC amplification and deletion of MTAP, CDKN2A, CDKN2B, and ELAVL2 in an acute myeloid leukemia characterized by oligonucleotide-array comparative genomic hybridization. Cancer Genet. Cytogenet. 183, 117–120 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Enciso-Mora, V. et al. A genome-wide association study of Hodgkin’s lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat. Genet. 42, 1126–1130 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schiffman, J. D. et al. Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res. 70, 512–519 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yu, J. et al. The long noncoding RNAs PVT1 and uc002mbe.2 in sera provide a new supplementary method for hepatocellular carcinoma diagnosis. Medicine 95, e4436 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Song, J. et al. Long non-coding RNA PVT1 promotes glycolysis and tumor progression by regulating miR-497/HK2 axis in osteosarcoma. Biochem. Biophys. Res. Commun. 490, 217–224 (2017).

    Article  CAS  PubMed  Google Scholar 

  81. Sun, L. et al. H19 promotes aerobic glycolysis, proliferation, and immune escape of gastric cancer cells through the microRNA-519d-3p/lactate dehydrogenase A axis. Cancer Sci. 112, 2245–2259 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yang, J. et al. Glycolysis reprogramming in cancer-associated fibroblasts promotes the growth of oral cancer through the lncRNA H19/miR-675-5p/PFKFB3 signaling pathway. Int. J. Oral. Sci. 13, 12 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Boyerinas, B. et al. Identification of Let-7–regulated oncofetal genes. Cancer Res. 68, 2587–2591 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Nielsen, J. et al. A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol. Cell Biol. 19, 1262–1270 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Yen, B. L. et al. Brief report — human embryonic stem cell-derived mesenchymal progenitors possess strong immunosuppressive effects toward natural killer cells as well as T lymphocytes. Stem Cell 27, 451–456 (2009).

    Article  Google Scholar 

  86. Hsu, J.-M. et al. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat. Commun. 9, 1908 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Corgnac, S. et al. Cancer stem-like cells evade CD8+ CD103+ tumor-resident memory T (TRM) lymphocytes by initiating an epithelial-to-mesenchymal transition program in a human lung tumor model. J. Immunother. Cancer 10, e004527 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Miao, Y. et al. Adaptive immune resistance emerges from tumor-initiating stem cells. Cell 177, 1172–1186.e14 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Mintz, B. & Illmensee, K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc. Natl Acad. Sci. USA 72, 3585–3589 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Pierce, G. B., Pantazis, C. G., Caldwell, J. E. & Wells, R. S. Specificity of the control of tumor formation by the blastocyst. Cancer Res. 42, 1082–1087 (1982).

    CAS  PubMed  Google Scholar 

  91. Lee, L. M. J., Seftor, E. A., Bonde, G., Cornell, R. A. & Hendrix, M. J. C. The fate of human malignant melanoma cells transplanted into zebrafish embryos: assessment of migration and cell division in the absence of tumor formation. Dev. Dyn. 233, 1560–1570 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Young, M. D. et al. Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science 361, 594–599 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Li, H. et al. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat. Genet. 49, 708–718 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Coorens, T. H. H. et al. Embryonal precursors of Wilms tumor. Science 366, 1247–1251 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Behjati, S., Gilbertson, R. J. & Pfister, S. M. Maturation block in childhood cancer. Cancer Discov. 11, 542–544 (2021).

    Article  PubMed  Google Scholar 

  97. Jessa, S. et al. Stalled developmental programs at the root of pediatric brain tumors. Nat. Genet. 51, 1702–1713 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dhimolea, E. et al. An embryonic diapause-like adaptation with suppressed Myc activity enables tumor treatment persistence. Cancer Cell 39, 240–256.e11 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Rehman, S. K. et al. Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell 184, 226–242.e21 (2021).

    Article  CAS  PubMed  Google Scholar 

  100. Elenbaas, B. & Weinberg, R. A. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp. Cell Res. 264, 169–184 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Cassetta, L. & Pollard, J. W. Targeting macrophages: therapeutic approaches in cancer. Nat. Rev. Drug Discov. 17, 887–904 (2018).

    Article  CAS  PubMed  Google Scholar 

  102. Mulder, K. et al. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity 54, 1883–1900.e5 (2021).

    Article  CAS  PubMed  Google Scholar 

  103. Peng, H. et al. Metabolic reprogramming of vascular endothelial cells: basic research and clinical applications. Front. Cell Dev. Biol. 9, 626047 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Becker, L. M. et al. Epigenetic reprogramming of cancer-associated fibroblasts deregulates glucose metabolism and facilitates progression of breast cancer. Cell Rep. 31, 107701 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wei, J., Zheng, W., Chapman, N. M., Geiger, T. L. & Chi, H. T cell metabolism in homeostasis and cancer immunity. Curr. Opin. Biotechnol. 68, 240–250 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Verma, V. et al. MEK inhibition reprograms CD8+ T lymphocytes into memory stem cells with potent antitumor effects. Nat. Immunol. 22, 53–66 (2021).

    Article  CAS  PubMed  Google Scholar 

  107. Tlsty, T. D. Stromal cells can contribute oncogenic signals. Semin. Cancer Biol. 11, 97–104 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Park, C. C., Bissell, M. J. & Barcellos-Hoff, M. H. The influence of the microenvironment on the malignant phenotype. Mol. Med. Today 6, 324–329 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Li, G. et al. Function and regulation of melanoma–stromal fibroblast interactions: when seeds meet soil. Oncogene 22, 3162–3171 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Cassetta, L. et al. Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell 35, 588–602.e10 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Colotta, F., Allavena, P., Sica, A., Garlanda, C. & Mantovani, A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30, 1073–1081 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Bian, Z. et al. Deciphering human macrophage development at single-cell resolution. Nature 582, 571–576 (2020).

    Article  CAS  PubMed  Google Scholar 

  113. Liu, Z. et al. Fate mapping via ms4a3-expression history traces monocyte-derived cells. Cell 178, 1509–1525.e19 (2019).

    Article  CAS  PubMed  Google Scholar 

  114. Ginhoux, F. & Jung, S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat. Rev. Immunol. 14, 392–404 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Blériot, C., Chakarov, S. & Ginhoux, F. Determinants of resident tissue macrophage identity and function. Immunity 52, 957–970 (2020).

    Article  PubMed  Google Scholar 

  116. Hashimoto, D., Miller, J. & Merad, M. Dendritic cell and macrophage heterogeneity in vivo. Immunity 35, 323–335 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Bain, C. C. et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat. Immunol.15, 929–937 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Franklin, R. A. et al. The cellular and molecular origin of tumor-associated macrophages. Science 344, 921–925 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhu, Y. et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 323–338.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Lavine, K. J. et al. Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc. Natl Acad. Sci. USA 111, 16029–16034 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Guilliams, M. et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med. 210, 1977–1992 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hoeffel, G. et al. C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Schneider, C. et al. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat. Immunol. 15, 1026–1037 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Cheng, S. et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell 184, 792–809.e23 (2021).

    Article  CAS  PubMed  Google Scholar 

  127. Guilliams, M. et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell 185, 379–396.e38 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ramos, R. N. et al. Tissue-resident FOLR2+ macrophages associate with CD8+ T cell infiltration in human breast cancer. Cell 185, 1189–1207.e25 (2022).

    Article  Google Scholar 

  129. Schor, S. L. et al. Migration-stimulating factor: a genetically truncated onco-fetal fibronectin isoform expressed by carcinoma and tumor-associated stromal cells. Cancer Res. 63, 8827–8836 (2003).

    CAS  PubMed  Google Scholar 

  130. Schor, S. L. et al. Mechanism of action of the migration stimulating factor produced by fetal and cancer patient fibroblasts: effect on hyaluronic acid synthesis. Vitr. Cell Dev. Biol. 25, 737–746 (1989).

    Article  CAS  Google Scholar 

  131. Schor, S. L. & Schor, A. M. Phenotypic and genetic alterations in mammary stroma: implications for tumour progression. Breast Cancer Res. 3, 373–379 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Solinas, G. et al. Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility. J. Immunol. 185, 642–652 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Bonnardel, J. et al. Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity 51, 638–654.e9 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Sakai, M. et al. Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity. Immunity 51, 655–670.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhou, X. et al. Circuit design features of a stable two-cell system. Cell 172, 744–757.e17 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Rantakari, P. et al. Fetal liver endothelium regulates the seeding of tissue-resident macrophages. Nature 538, 392–396 (2016).

    Article  CAS  PubMed  Google Scholar 

  137. Rantakari, P. et al. The endothelial protein PLVAP in lymphatics controls the entry of lymphocytes and antigens into lymph nodes. Nat. Immunol. 16, 386–396 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Popescu, D.-M. et al. Decoding human fetal liver haematopoiesis. Nature 574, 365–371 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Aizarani, N. et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 572, 199–204 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kumar, V. et al. Single-cell atlas of lineage states, tumor microenvironment and subtype-specific expression programs in gastric cancer. Cancer Discov. 12, 670–691 (2021).

    Article  Google Scholar 

  141. Terkelsen, M. K. et al. Transcriptional dynamics of hepatic sinusoid-associated cells after liver injury. Hepatology 72, 2119–2133 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Gomes, R. N., Manuel, F. & Nascimento, D. S. The bright side of fibroblasts: molecular signature and regenerative cues in major organs. NPJ Regen. Med. 6, 43 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Chen, X. & Song, E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat. Rev. Drug Discov. 18, 99–115 (2019).

    Article  CAS  PubMed  Google Scholar 

  144. Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

    Article  CAS  PubMed  Google Scholar 

  145. Bu, L. et al. Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment. Oncogene 38, 4887–4901 (2019).

    Article  CAS  PubMed  Google Scholar 

  146. Bertero, T. et al. Tumor-stroma mechanics coordinate amino acid availability to sustain tumor growth and malignancy. Cell Metab. 29, 124–140.e10 (2019).

    Article  CAS  PubMed  Google Scholar 

  147. Schor, S. L. et al. Occurrence of a fetal fibroblast phenotype in familial breast cancer. Int. J. Cancer 37, 831–836 (1986).

    Article  CAS  PubMed  Google Scholar 

  148. Haggie, J. A., Howell, A., Sellwood, R. A., Birch, J. M. & Schor, S. L. Fibroblasts from relatives of patients with hereditary breast cancer show fetal-like behaviour in vitro. Lancet 329, 1455–1457 (1987).

    Article  Google Scholar 

  149. Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Aegerter, H. et al. Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection. Nat. Immunol. 21, 145–157 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Machiels, B. et al. A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat. Immunol. 18, 1310–1320 (2017).

    Article  CAS  PubMed  Google Scholar 

  153. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Zhang, Y. et al. Dynamic expression of m6A regulators during multiple human tissue development and cancers. Front. Cell Dev. Biol. 8, 629030 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Zaidi, S. K. et al. Bivalent epigenetic control of oncofetal gene expression in cancer. Mol. Cell Biol. 37, e00352-17 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. Azuara, V. et al. Chromatin signatures of pluripotent cell lines. Nat. Cell Biol. 8, 532–538 (2006).

    Article  CAS  PubMed  Google Scholar 

  158. Ikeda, N. et al. Emergence of immunoregulatory Ym1+Ly6Chi monocytes during recovery phase of tissue injury. Sci. Immunol. 3, eaat0207 (2018).

    Article  PubMed  Google Scholar 

  159. Laval, Bde et al. C/EBPβ-dependent epigenetic memory induces trained immunity in hematopoietic stem cells. Cell Stem Cell 26, 657–674.e8 (2020).

    Article  PubMed  Google Scholar 

  160. Bastola, S. et al. Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy. Nat. Commun. 11, 4660 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Darmanis, S. et al. Single-cell RNA-seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell Rep. 21, 1399–1410 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Casanova-Acebes, M. et al. Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells. Nature 595, 578–584 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Yao, Y., Li, F., Huang, J., Jin, J. & Wang, H. Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development. Exp. Hematol. Oncol. 10, 39 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Schepers, K., Campbell, T. B. & Passegué, E. Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell 16, 254–267 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Lewis, S. M. et al. Spatial omics and multiplexed imaging to explore cancer biology. Nat. Methods 18, 997–1012 (2021).

    Article  CAS  PubMed  Google Scholar 

  166. Fawkner-Corbett, D. et al. Spatiotemporal analysis of human intestinal development at single-cell resolution. Cell 184, 810–826.e23 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. diSibio, G. & French, S. W. Metastatic patterns of cancers: results from a large autopsy study. Arch. Pathol. Lab. Med. 132, 931–939 (2008).

    Article  PubMed  Google Scholar 

  169. Durante, M. A. et al. Single-cell analysis reveals new evolutionary complexity in uveal melanoma. Nat. Commun. 11, 496 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Mora, J. What is a pediatric tumor? Clin. Oncol. Adolesc. Young-. Adults 2012, 7–15 (2012).

    Article  Google Scholar 

  171. Gale, K. B. et al. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proc. Natl Acad. Sci. USA 94, 13950–13954 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Greaves, M. A causal mechanism for childhood acute lymphoblastic leukaemia. Nat. Rev. Cancer 18, 471–484 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Gargett, C. E., Nguyen, H. P. T. & Ye, L. Endometrial regeneration and endometrial stem/progenitor cells. Rev. Endocr. Metab. Disord. 13, 235–251 (2012).

    Article  CAS  PubMed  Google Scholar 

  174. Garcia-Alonso, L. et al. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro. Nat. Genet. 53, 1698–1711 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).

    Article  CAS  PubMed  Google Scholar 

  176. Cheng, A.-L. et al. IMbrave150: efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann. Oncol. 30, ix186–ix187 (2019).

    Article  Google Scholar 

  177. Finn, R. S. et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo)+bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J. Clin. Oncol. 39, 267–267 (2021).

    Article  Google Scholar 

  178. Pachnis, V., Belayew, A. & Tilghman, S. M. Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes. Proc. Natl Acad. Sci. USA 81, 5523–5527 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

    Article  CAS  PubMed  Google Scholar 

  180. Tang, F. et al. mRNA-seq whole-transcriptome analysis of a single cell. Nat. Methods 6, 377–382 (2009).

    Article  CAS  PubMed  Google Scholar 

  181. Ståhl, P. L. et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 353, 78–82 (2016).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank D. Ackerman (Insight Editing London) for editing the manuscript during preparation. A.S. is supported by funding from the National Health and Medical Research Council (NHMRC) Ideas Grant (APP2010795), a Perkins–Curtin start-up fellowship and the Cancer Research Trust (CRT) Program Grant to the Liver Cancer Collaborative (LCC). J.C. is supported by a fellowship from the NHMRC Ideas Grant (APP2010795). F.G. is supported by the Singapore Agency for Science, Technology and Research (A*STAR) Biomedical Research Council Use-Inspired Basic Research (UIBR) Award, the Singapore National Research Foundation Senior Investigatorship (NRFI2017-02), the Fondation ARC “Leaders de demain” and the Fondation Gustave Roussy.

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A.S. and F.G. conceptualized the Perspective. A.S., C.B. and F.G. contributed equally to all other aspects of the article. J.C. contributed substantially to discussion of the content, writing the article and review of the manuscript before submission.

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Correspondence to Ankur Sharma or Florent Ginhoux.

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Sharma, A., Blériot, C., Currenti, J. et al. Oncofetal reprogramming in tumour development and progression. Nat Rev Cancer 22, 593–602 (2022). https://doi.org/10.1038/s41568-022-00497-8

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