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Stem cell fate in cancer growth, progression and therapy resistance

Nature Reviews Cancervolume 18pages669680 (2018) | Download Citation


Although we have come a long way in our understanding of the signals that drive cancer growth, and how these signals can be targeted, effective control of this disease remains a key scientific and medical challenge. The therapy resistance and relapse that are commonly seen are driven in large part by the inherent heterogeneity within cancers that allows drugs to effectively eliminate some, but not all, malignant cells. Here, we focus on the fundamental drivers of this heterogeneity by examining emerging evidence that shows that these traits are often controlled by the disruption of normal cell fate and aberrant adoption of stem cell signals. We discuss how undifferentiated cells are preferentially primed for transformation and often serve as the cell of origin for cancers. We also consider evidence showing that activation of stem cell programmes in cancers can lead to progression, therapy resistance and metastatic growth and that targeting these attributes may enable better control over a difficult disease.

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  1. 1.

    Hunger, S. P., Winick, N. J., Sather, H. N. & Carroll, W. L. Therapy of low-risk subsets of childhood acute lymphoblastic leukemia: when do we say enough? Pediatr. Blood Cancer 45, 876–880 (2005).

  2. 2.

    Hodgson, D. C., Hudson, M. M. & Constine, L. S. Pediatric hodgkin lymphoma: maximizing efficacy and minimizing toxicity. Semin. Radiat. Oncol. 17, 230–242 (2007).

  3. 3.

    Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

  4. 4.

    Gibson, P. et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095–1099 (2010).

  5. 5.

    Lapouge, G. et al. Identifying the cellular origin of squamous skin tumors. Proc. Natl Acad. Sci. USA 108, 7431–7436 (2011).

  6. 6.

    Xu, X. et al. Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma. Proc. Natl Acad. Sci. USA 109, 4910–4915 (2012).

  7. 7.

    Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

  8. 8.

    Daley, G. Q., Van Etten, R. A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830 (1990).

  9. 9.

    Whang, J., Frei, E. 3rd, Tjio, J. H., Carbone, P. P. & Brecher, G. The distribution of the Philadelphia chromosome in patients with chronic myelogenous leukemia. Blood 22, 664–673 (1963).

  10. 10.

    Krivtsov, A. V. et al. Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. Leukemia 27, 852–860 (2013).

  11. 11.

    Shlush, L. I. et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).

  12. 12.

    Blaas, L. et al. Lgr6 labels a rare population of mammary gland progenitor cells that are able to originate luminal mammary tumours. Nat. Cell Biol. 18, 1346–1356 (2016).

  13. 13.

    Zhao, C. et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12, 528–541 (2007).

  14. 14.

    Latil, M. et al. Cell-type-specific chromatin states differentially prime squamous cell carcinoma tumor-initiating cells for epithelial to mesenchymal transition. Cell Stem Cell 20, 191–204 (2017).

  15. 15.

    Alcantara Llaguno, S. R. et al. Adult lineage-restricted CNS progenitors specify distinct glioblastoma subtypes. Cancer Cell 28, 429–440 (2015).

  16. 16.

    Alcantara Llaguno, S. et al. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15, 45–56 (2009).

  17. 17.

    Yang, Z. J. et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14, 135–145 (2008).

  18. 18.

    Schuller, U. et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14, 123–134 (2008).

  19. 19.

    Xie, W. et al. DNA methylation patterns separate senescence from transformation potential and indicate cancer risk. Cancer Cell 33, 309–321 (2018).

  20. 20.

    Yu, Y. et al. Targeting the senescence-overriding cooperative activity of structurally unrelated H3K9 demethylases in melanoma. Cancer Cell 33, 322–336 (2018).

  21. 21.

    Kaufman, C. K. et al. A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation. Science 351, aad2197 (2016). This study illustrates that the epigenetic state can act as a determining factor for the cell of origin in a zebrafish model of melanoma.

  22. 22.

    Gilbert, N. et al. Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibers. Cell 118, 555–566 (2004).

  23. 23.

    Hoadley, K. A. et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 173, 291–304 (2018).

  24. 24.

    Vaz, M. et al. Chronic cigarette smoke-induced epigenomic changes precede sensitization of bronchial epithelial cells to single-step transformation by KRAS mutations. Cancer Cell 32, 360–376 (2017).

  25. 25.

    Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996).

  26. 26.

    Cho, Y. J. et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J. Clin. Oncol. 29, 1424–1430 (2011).

  27. 27.

    Hahn, H. et al. Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).

  28. 28.

    Ellisen, L. W. et al. TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649–661 (1991).

  29. 29.

    Gonzalez, M. E. et al. EZH2 expands breast stem cells through activation of NOTCH1 signaling. Proc. Natl Acad. Sci. USA 111, 3098–3103 (2014).

  30. 30.

    Miyamoto, Y. et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3, 565–576 (2003).

  31. 31.

    Valencia, A. et al. Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia. Leukemia 23, 1658–1666 (2009).

  32. 32.

    Yuan, X. et al. Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett. 369, 20–27 (2015).

  33. 33.

    Ashihara, E., Takada, T. & Maekawa, T. Targeting the canonical Wnt/beta-catenin pathway in hematological malignancies. Cancer Sci. 106, 665–671 (2015).

  34. 34.

    Di Giacomo, D. et al. Blast crisis Ph+ chronic myeloid leukemia with NUP98/HOXA13 up-regulating MSI2. Mol. Cytogenet. 7, 42 (2014).

  35. 35.

    Ito, T. et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 466, 765–768 (2010).

  36. 36.

    Kharas, M. G. et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat. Med. 16, 903–908 (2010).

  37. 37.

    Yamashita, Y. et al. Array-based genomic resequencing of human leukemia. Oncogene 29, 3723–3731 (2010).

  38. 38.

    Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).

  39. 39.

    Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2011).

  40. 40.

    Tadokoro, Y., Ema, H., Okano, M., Li, E. & Nakauchi, H. De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J. Exp. Med. 204, 715–722 (2007).

  41. 41.

    Mayle, A. et al. Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. Blood 125, 629–638 (2015).

  42. 42.

    Hajkova, H. et al. Decreased DNA methylation in acute myeloid leukemia patients with DNMT3A mutations and prognostic implications of DNA methylation. Leuk. Res. 36, 1128–1133 (2012).

  43. 43.

    Yan, X. J. et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat. Genet. 43, 309–315 (2011).

  44. 44.

    Kagara, N. et al. Epigenetic regulation of cancer stem cell genes in triple-negative breast cancer. Am. J. Pathol. 181, 257–267 (2012).

  45. 45.

    Gopisetty, G., Xu, J., Sampath, D., Colman, H. & Puduvalli, V. K. Epigenetic regulation of CD133/PROM1 expression in glioma stem cells by Sp1/myc and promoter methylation. Oncogene 32, 3119–3129 (2013).

  46. 46.

    Zhang, W. & Xu, J. DNA methyltransferases and their roles in tumorigenesis. Biomark. Res. 5, 1 (2017).

  47. 47.

    Martin, M. et al. Dynamic imbalance between cancer cell subpopulations induced by transforming growth factor beta (TGF-β) is associated with a DNA methylome switch. BMC Genomics 15, 435 (2014).

  48. 48.

    Weis, B. et al. Inhibition of intestinal tumor formation by deletion of the DNA methyltransferase 3a. Oncogene 34, 1822–1830 (2015).

  49. 49.

    Tsai, H. C. et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21, 430–446 (2012).

  50. 50.

    Kondo, Y. Targeting histone methyltransferase EZH2 as cancer treatment. J. Biochem. 156, 249–257 (2014).

  51. 51.

    Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524–528 (2011). This study identifies the epigenetic regulator BRD4 as critical in the maintenance of CSCs in AML.

  52. 52.

    Riggs, M. G., Whittaker, R. G., Neumann, J. R. & Ingram, V. M. n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature 268, 462–464 (1977).

  53. 53.

    Fiskus, W. et al. Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol. Cancer Ther. 13, 1142–1154 (2014).

  54. 54.

    Pei, Y. et al. HDAC and PI3K antagonists cooperate to inhibit growth of MYC-driven medulloblastoma. Cancer Cell 29, 311–323 (2016).

  55. 55.

    Fox, R. G. et al. Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. Nature 534, 407–411 (2016). This study shows that the stem cell fate determinant MSI is a critical mediator of pancreatic cancer progression and lethality.

  56. 56.

    Mazur, P. K. et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat. Med. 21, 1163–1171 (2015).

  57. 57.

    Shu, S. et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529, 413–417 (2016).

  58. 58.

    Zhang, B. et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 17, 427–442 (2010).

  59. 59.

    Pathania, R. et al. DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nat. Commun. 6, 6910 (2015).

  60. 60.

    Bello, B., Reichert, H. & Hirth, F. The brain tumor gene negatively regulates neural progenitor cell proliferation in the larval central brain of Drosophila. Development 133, 2639–2648 (2006).

  61. 61.

    Gateff, E. Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 200, 1448–1459 (1978).

  62. 62.

    Betschinger, J., Mechtler, K. & Knoblich, J. A. Asymmetric segregation of the tumor suppressor brat regulates self-renewal in Drosophila neural stem cells. Cell 124, 1241–1253 (2006).

  63. 63.

    Bowman, S. K., Neumuller, R. A., Novatchkova, M., Du, Q. & Knoblich, J. A. The Drosophila NuMA Homolog Mud regulates spindle orientation in asymmetric cell division. Dev. Cell 10, 731–742 (2006).

  64. 64.

    Wu, M. et al. Imaging hematopoietic precursor division in real time. Cell Stem Cell 1, 541–554 (2007).

  65. 65.

    Zimdahl, B. et al. Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia. Nat. Genet. 46, 245–252 (2014).

  66. 66.

    Cicalese, A. et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138, 1083–1095 (2009).

  67. 67.

    Sheng, W. et al. Musashi2 promotes the development and progression of pancreatic cancer by down-regulating Numb protein. Oncotarget 8, 14359–14373 (2016).

  68. 68.

    Shen, Q., Zhong, W., Jan, Y. N. & Temple, S. Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development 129, 4843–4853 (2002).

  69. 69.

    Sugiarto, S. et al. Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell 20, 328–340 (2011).

  70. 70.

    Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002).

  71. 71.

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

  72. 72.

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

  73. 73.

    Jolly, M. K., Ware, K. E., Gilja, S., Somarelli, J. A. & Levine, H. EMT and MET: necessary or permissive for metastasis? Mol. Oncol. 11, 755–769 (2017).

  74. 74.

    Aiello, N. M. et al. EMT subtype influences epithelial plasticity and mode of cell migration. Dev. Cell 45, 681–695 (2018).

  75. 75.

    Sampson, V. B. et al. Wilms’ tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma. PLOS ONE 9, e102041 (2014).

  76. 76.

    Schliekelman, M. J. et al. Molecular portraits of epithelial, mesenchymal, and hybrid states in lung adenocarcinoma and their relevance to survival. Cancer Res. 75, 1789–1800 (2015).

  77. 77.

    Grosse-Wilde, A. et al. Stemness of the hybrid epithelial/mesenchymal state in breast cancer and its association with poor survival. PLOS ONE 10, e0126522 (2015).

  78. 78.

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

  79. 79.

    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).

  80. 80.

    Balic, M. et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin. Cancer Res. 12, 5615–5621 (2006).

  81. 81.

    Grillet, F. et al. Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture. Gut 66, 1802–1810 (2017).

  82. 82.

    Charafe-Jauffret, E. et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 69, 1302–1313 (2009).

  83. 83.

    Dieter, S. M. et al. Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. Cell Stem Cell 9, 357–365 (2011).

  84. 84.

    Aktas, B. et al. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 11, R46 (2009).

  85. 85.

    Baccelli, I. et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat. Biotechnol. 31, 539–544 (2013).

  86. 86.

    Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

  87. 87.

    Polyak, K. & Weinberg, R. A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9, 265–273 (2009).

  88. 88.

    Raimondi, C. et al. Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res. Treat. 130, 449–455 (2011).

  89. 89.

    Shipitsin, M. et al. Molecular definition of breast tumor heterogeneity. Cancer Cell 11, 259–273 (2007).

  90. 90.

    Beck, B. et al. Different levels of Twist1 regulate skin tumor initiation, stemness, and progression. Cell Stem Cell 16, 67–79 (2015).

  91. 91.

    Fan, F. et al. Overexpression of snail induces epithelial-mesenchymal transition and a cancer stem cell-like phenotype in human colorectal cancer cells. Cancer Med. 1, 5–16 (2012).

  92. 92.

    Kurrey, N. K. et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27, 2059–2068 (2009).

  93. 93.

    Burk, U. et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 9, 582–589 (2008).

  94. 94.

    Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008). This study links EMT and stem cells by reporting that EMT leads to the acquisition of stem cell traits, while stem cells themselves express markers of EMT.

  95. 95.

    Morel, A. P. et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLOS ONE 3, e2888 (2008).

  96. 96.

    Wellner, U. et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell Biol. 11, 1487–1495 (2009).

  97. 97.

    Oskarsson, T., Batlle, E. & Massague, J. Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14, 306–321 (2014).

  98. 98.

    Hermann, P. C. et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1, 313–323 (2007).

  99. 99.

    Pang, R. et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 6, 603–615 (2010).

  100. 100.

    Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).

  101. 101.

    Tirosh, I. et al. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature 539, 309–313 (2016).

  102. 102.

    Bakker, B. et al. Single-cell sequencing reveals karyotype heterogeneity in murine and human malignancies. Genome Biol. 17, 115 (2016).

  103. 103.

    Turner, K. M. et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543, 122–125 (2017).

  104. 104.

    Pao, W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLOS Med. 2, e73 (2005).

  105. 105.

    Ding, L. et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481, 506–510 (2012).

  106. 106.

    Patch, A. M. et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 521, 489–494 (2015).

  107. 107.

    Lee, M. C. et al. Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing. Proc. Natl Acad. Sci. USA 111, E4726–E4735 (2014).

  108. 108.

    Kurtova, A. V. et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature 517, 209–213 (2015).

  109. 109.

    Kim, C. et al. Chemoresistance evolution in triple-negative breast cancer delineated by single-cell sequencing. Cell 173, 879–893 (2018). Using single-cell sequencing, this study shows that therapy resistance in triple-negative breast cancer is driven by a population of pre-existing clones and not through the progressive accumulation of oncogenic mutations.

  110. 110.

    Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).

  111. 111.

    Hata, A. N. et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 22, 262–269 (2016). This study demonstrates that the epigenetic state can confer a drug-tolerant state, which then allows for genomic evolution leading to drug resistance.

  112. 112.

    Dean, M. Cancer stem cells: implications for cancer causation and therapy resistance. Discov. Med. 5, 278–282 (2005).

  113. 113.

    Blanpain, C., Mohrin, M., Sotiropoulou, P. A. & Passegue, E. DNA-damage response in tissue-specific and cancer stem cells. Cell Stem Cell 8, 16–29 (2011).

  114. 114.

    Hovinga, K. E. et al. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells 28, 1019–1029 (2010).

  115. 115.

    Chaudhary, P. M. & Roninson, I. B. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66, 85–94 (1991).

  116. 116.

    Zhou, S. et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat. Med. 7, 1028–1034 (2001).

  117. 117.

    Lin, T., Islam, O. & Heese, K. ABC transporters, neural stem cells and neurogenesis—a different perspective. Cell Res. 16, 857–871 (2006).

  118. 118.

    Hirschmann-Jax, C. et al. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc. Natl Acad. Sci. USA 101, 14228–14233 (2004).

  119. 119.

    Stupp, R. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10, 459–466 (2009).

  120. 120.

    Singh, S. K. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821–5828 (2003).

  121. 121.

    Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).

  122. 122.

    Dent, P. et al. CHK1 inhibitors in combination chemotherapy: thinking beyond the cell cycle. Mol. Interv. 11, 133–140 (2011).

  123. 123.

    Ong, D. S. T. et al. PAF promotes stemness and radioresistance of glioma stem cells. Proc. Natl Acad. Sci. USA 114, E9086–E9095 (2017).

  124. 124.

    Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat. Med. 2, 561–566 (1996).

  125. 125.

    Kimura, S. Current status of ABL tyrosine kinase inhibitors stop studies for chronic myeloid leukemia. Stem Cell. Investig. 3, 36 (2016).

  126. 126.

    Bhatia, R. et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101, 4701–4707 (2003).

  127. 127.

    Chomel, J. C. et al. Leukemic stem cell persistence in chronic myeloid leukemia patients with sustained undetectable molecular residual disease. Blood 118, 3657–3660 (2011).

  128. 128.

    Graham, S. M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99, 319–325 (2002).

  129. 129.

    Corbin, A. S. et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J. Clin. Invest. 121, 396–409 (2011).

  130. 130.

    Jabbour, E. J., Cortes, J. E. & Kantarjian, H. M. Tyrosine kinase inhibition: a therapeutic target for the management of chronic-phase chronic myeloid leukemia. Expert Rev. Anticancer Ther. 13, 1433–1452 (2013).

  131. 131.

    Chen, Y., Hu, Y., Zhang, H., Peng, C. & Li, S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat. Genet. 41, 783–792 (2009).

  132. 132.

    Hu, Y., Chen, Y., Douglas, L. & Li, S. beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia 23, 109–116 (2009).

  133. 133.

    Zhao, C. et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458, 776–779 (2009).

  134. 134.

    Shien, K. et al. Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer Res. 73, 3051–3061 (2013).

  135. 135.

    Arasada, R. R., Amann, J. M., Rahman, M. A., Huppert, S. S. & Carbone, D. P. EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling. Cancer Res. 74, 5572–5584 (2014).

  136. 136.

    Hu, S. et al. Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency. Sci. Transl Med. 9, eaag0339 (2017).

  137. 137.

    Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

  138. 138.

    Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).

  139. 139.

    Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).

  140. 140.

    Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

  141. 141.

    Malta, T. M. et al. Machine learning identifies stemness features associated with oncogenic dedifferentiation. Cell 173, 338–354 (2018).

  142. 142.

    Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).

  143. 143.

    Ji, R. R. et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol. Immunother. 61, 1019–1031 (2012).

  144. 144.

    Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015). This study demonstrates that stem cell signals within a tumour can lead to the exclusion of T cell infiltration and resistance to checkpoint inhibitor therapy, illustrating the impact of stem cell signalling on the microenvironment to promote aggressive disease.

  145. 145.

    Cheah, M. T. et al. CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer. Proc. Natl Acad. Sci. USA 112, 4725–4730 (2015).

  146. 146.

    Calabrese, C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82 (2007).

  147. 147.

    Bao, S. et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 66, 7843–7848 (2006).

  148. 148.

    Folkins, C. et al. Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Cancer Res. 69, 7243–7251 (2009).

  149. 149.

    Charles, N. et al. Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell 6, 141–152 (2010).

  150. 150.

    Pietras, A. et al. Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth. Cell Stem Cell 14, 357–369 (2014).

  151. 151.

    Vredenburgh, J. J. et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin. Cancer Res. 13, 1253–1259 (2007).

  152. 152.

    Das, B. et al. Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction. Stem Cells 26, 1818–1830 (2008).

  153. 153.

    Heddleston, J. M., Li, Z., McLendon, R. E., Hjelmeland, A. B. & Rich, J. N. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 8, 3274–3284 (2009).

  154. 154.

    Chiou, S. H. et al. BLIMP1 induces transient metastatic heterogeneity in pancreatic cancer. Cancer Discov. 7, 1184–1199 (2017).

  155. 155.

    Tammela, T. et al. A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma. Nature 545, 355–359 (2017). This study demonstrates how non-stem cells of the niche utilize stem cell signals to drive the tumorgenicity of neighbouring responder cells, illustrating the influence of the microenvironment on promoting aggressive disease through the use of stem cell signals.

  156. 156.

    Wang, X. et al. Reciprocal signaling between glioblastoma stem cells and differentiated tumor cells promotes malignant progression. Cell Stem Cell 22, 514–528 (2018).

  157. 157.

    Su, S. et al. CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172, 841–856 (2018). In this study, cancer-associated fibroblasts are shown to support the CSC niche and contribute to therapy resistance, a key example of how the microenvironment impacts aggressive disease.

  158. 158.

    Chen, W. J. et al. Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat. Commun. 5, 3472 (2014).

  159. 159.

    Sneddon, J. B. et al. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Proc. Natl Acad. Sci. USA 103, 14842–14847 (2006).

  160. 160.

    Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).

  161. 161.

    Bajaj, J. et al. CD98-mediated adhesive signaling enables the establishment and propagation of acute myelogenous leukemia. Cancer Cell 30, 792–805 (2016).

  162. 162.

    Kwon, H. Y. et al. Tetraspanin 3 is required for the development and propagation of acute myelogenous leukemia. Cell Stem Cell 17, 152–164 (2015).

  163. 163.

    Passaro, D. et al. CXCR4 is required for leukemia-initiating cell activity in T cell acute lymphoblastic leukemia. Cancer Cell 27, 769–779 (2015).

  164. 164.

    Ebinger, S. et al. Characterization of rare, dormant, and therapy-resistant cells in acute lymphoblastic leukemia. Cancer Cell 30, 849–862 (2016).

  165. 165.

    Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009). This is the first study to report the development of organoids that recapitulate the stem cell hierarchy of the original tissue.

  166. 166.

    Drost, J. & Clevers, H. Organoids in cancer research. Nat. Rev. Cancer 18, 407–418 (2018).

  167. 167.

    Roerink, S. F. et al. Intra-tumour diversification in colorectal cancer at the single-cell level. Nature 556, 457–462 (2018).

  168. 168.

    Boj, S. F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338 (2015).

  169. 169.

    Tiriac, H. et al. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discov. (2018).

  170. 170.

    Sachs, N. et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172, 373–386 (2018).

  171. 171.

    Broutier, L. et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat. Med. 23, 1424–1435 (2017).

  172. 172.

    Lee, S. H. et al. Tumor evolution and drug response in patient-derived organoid models of bladder cancer. Cell 173, 515–528 (2018).

  173. 173.

    Danial, C., Sarin, K. Y., Oro, A. E. & Chang, A. L. An investigator-initiated open-label trial of sonidegib in advanced basal cell carcinoma patients resistant to vismodegib. Clin. Cancer Res. 22, 1325–1329 (2016).

  174. 174.

    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).

  175. 175.

    Chang, A. L. et al. Safety and efficacy of vismodegib in patients with basal cell carcinoma nevus syndrome: pooled analysis of two trials. Orphanet J. Rare Dis. 11, 120 (2016).

  176. 176.

    Sekulic, A. et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N. Engl. J. Med. 366, 2171–2179 (2012).

  177. 177.

    Robinson, G. W. et al. Vismodegib exerts targeted efficacy against recurrent sonic hedgehog-subgroup medulloblastoma: results from phase II Pediatric Brain Tumor Consortium studies PBTC-025B and PBTC-032. J. Clin. Oncol. 33, 2646–2654 (2015).

  178. 178.

    Belani, C. P. et al. Vismodegib or cixutumumab in combination with standard chemotherapy for patients with extensive-stage small cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1508). Cancer 122, 2371–2378 (2016).

  179. 179.

    US National Library of Medicine. (2015).

  180. 180.

    US National Library of Medicine. (2017).

  181. 181.

    Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005–1009 (2000).

  182. 182.

    Atwood, S. X., Li, M., Lee, A., Tang, J. Y. & Oro, A. E. GLI activation by atypical protein kinase C ι /λ regulates the growth of basal cell carcinomas. Nature 494, 484–488 (2013).

  183. 183.

    Rimkus, T. K., Carpenter, R. L., Qasem, S., Chan, M. & Lo, H. W. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers 8, E22 (2016).

  184. 184.

    US National Library of Medicine. (2018).

  185. 185.

    Lyou, Y., Habowski, A. N., Chen, G. T. & Waterman, M. L. Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy. Br. J. Pharmacol. 174, 4589–4599 (2017).

  186. 186.

    US National Library of Medicine. (2017).

  187. 187.

    US National Library of Medicine. (2016).

  188. 188.

    Jimeno, A. et al. A first-in-human phase 1 study of the anti-cancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors. Clin. Cancer Res. 23, 7490–7497 (2017).

  189. 189.

    US National Library of Medicine. (2018).

  190. 190.

    Jain, P. et al. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: cohort study of 477 patients. Cancer 123, 4391–4402 (2017).

  191. 191.

    Knoblich, J. A. Mechanisms of asymmetric stem cell division. Cell 132, 583–597 (2008).

  192. 192.

    Knoblich, J. A. Asymmetric cell division: recent developments and their implications for tumour biology. Nat. Rev. Mol. Cell Biol. 11, 849–860 (2010).

  193. 193.

    Bajaj, J., Zimdahl, B. & Reya, T. Fearful symmetry: subversion of asymmetric division in cancer development and progression. Cancer Res. 75, 792–797 (2015).

  194. 194.

    Ito, K. & Hotta, Y. Proliferation pattern of postembryonic neuroblasts in the brain of Drosophila melanogaster. Dev. Biol. 149, 134–148 (1992).

  195. 195.

    Heidel, F. H. et al. The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML. J. Exp. Med. 210, 15–22 (2013).

  196. 196.

    He, L. et al. A microRNA component of the p53 tumour suppressor network. Nature 447, 1130–1134 (2007).

  197. 197.

    Bu, P. et al. A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. Cell Stem Cell 12, 602–615 (2013).

  198. 198.

    Li, Y. et al. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res. 69, 7569–7576 (2009).

  199. 199.

    Hwang, W. L. et al. MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells. Nat. Cell Biol. 16, 268–280 (2014).

  200. 200.

    Chen, G. et al. Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma. Cancer Res. 74, 4536–4548 (2014).

  201. 201.

    Wang, L. et al. A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division. eLife 5, e14620 (2016).

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The authors thank M. Kritzik for her help with the preparation of the manuscript. N.K.L. received support from US National Institutes of Health (NIH) grant T32 GM00752 and NIH National Research Service Individual Award F31 CA206416. A.G.B. received support from NIH grant R01 DK099335-S1 and NIH grant T32 CA121938. T.R. was supported by NIH grant R35 CA197699 and a Stand Up To Cancer–Cancer Research UK–Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (SU2C-AACR-DT-20-16).

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  1. Departments of Pharmacology and Medicine, San Diego School of Medicine, University of California, La Jolla, CA, USA

    • Nikki K. Lytle
    • , Alison G. Barber
    •  & Tannishtha Reya
  2. Sanford Consortium for Regenerative Medicine, San Diego School of Medicine, University of California, La Jolla, CA, USA

    • Nikki K. Lytle
    • , Alison G. Barber
    •  & Tannishtha Reya
  3. Moores Cancer Center, San Diego School of Medicine, University of California, La Jolla, CA, USA

    • Nikki K. Lytle
    • , Alison G. Barber
    •  & Tannishtha Reya


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N.K.L., A.G.B. and T.R. researched data for the article, wrote the article and reviewed or edited the manuscript before submission. N.K.L. and T.R. also made substantial contributions to the discussion of content.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Tannishtha Reya.


Stem cell

A cell that has the ability to perpetuate itself through self-renewal and to generate differentiated cells. Stem cells are relatively rare among other cell types and can be more quiescent and resistant to toxins and chemicals as well as display enhanced DNA repair.

Stem cell signals

Also called stem cell programmes, these are signals or gene expression programmes that are often associated with the undifferentiated state in embryonic and adult stem cells. Many stem cell programmes or signalling pathways are reactivated in oncogenesis.

Cancer stem cells

(CSCs). Cells with enriched functional capacity to drive tumour growth and recreate its heterogeneity. CSCs generally share many of the defining characteristics of normal stem cells, including increased drug resistance and DNA repair.

Asymmetric division

A method of cellular diversification via differential segregation and inheritance of fate determinants leading to differently fated daughter cells. Controlled asymmetric division can be critically important during development but can become dysregulated during tumour initiation and progression.

Symmetric division

A method of cell division in which fate determinants are equivalently segregated. The resulting pair of daughter cells can either be undifferentiated (symmetric renewal) or differentiated daughter cells (symmetric commitment).

Tumour heterogeneity

Here, refers to the presence of functionally distinct malignant cells within a tumour. Heterogeneity can be driven by different genomic, transcriptomic or epigenetic landscapes.

Side population

A small population of cells detected via flow cytometry that has increased dye efflux, a property that is associated with an increased expression of drug transporters. Functionally, the side population is enriched for cells with the ability to self-renew and differentiate. As these are key features of stem cells, the side population has traditionally been found to be enriched in stem cells and cancer stem cells.


A drug that inhibits the interaction of E3 ubiquitin-protein ligase MDM2 and p53 and is most effective on cells with wild-type p53 expression. Once released, wild-type p53 can induce cell cycle arrest and apoptosis.

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