EMT, CSCs, and drug resistance: the mechanistic link and clinical implications
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Levan, A. & Hauschka, T. S. Endomitotic reduplication mechanisms in ascites tumors of the mouse. J. Natl Cancer Inst. 14, 1–43 (1953).
Makino, S. Further evidence favoring the concept of the stem cell in ascites tumors of rats. Ann. NY Acad. Sci. 63, 818–830 (1956).
Prehn, R. T. Analysis of antigenic heterogeneity within individual 3-methylcholanthrene-induced mouse sarcomas. J. Natl Cancer Inst. 45, 1039–1045 (1970).
Alizadeh, A. A. et al. Toward understanding and exploiting tumor heterogeneity. Nat. Med. 21, 846–853 (2015).
Easwaran, H., Tsai, H. C. & Baylin, S. B. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol. Cell 54, 716–727 (2014).
Burrell, R. A., McGranahan, N., Bartek, J. & Swanton, C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501, 338–345 (2013).
Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).
Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
Bjerkvig, R., Tysnes, B. B., Aboody, K. S., Najbauer, J. & Terzis, A. J. The origin of the cancer stem cell: current controversies and new insights. Nat. Rev. Cancer 5, 899–904 (2005).
Avgustinova, A. & Benitah, S. A. Epigenetic control of adult stem cell function. Nat. Rev. Mol. Cell Biol. 17, 643–658 (2016).
Brabletz, T., Jung, A., Spaderna, S., Hlubek, F. & Kirchner, T. Migrating cancer stem cells — an integrated concept of malignant tumour progression. Nat. Rev. Cancer 5, 744–749 (2005).
Wicha, M. S., Liu, S. & Dontu, G. Cancer stem cells: an old idea — a paradigm shift. Cancer Res. 66, 1883–1890 (2006).
Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5, 275–284 (2005).
Clarke, M. F. et al. Cancer stem cells — perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66, 9339–9344 (2006).
Eyler, C. E. & Rich, J. N. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J. Clin. Oncol. 26, 2839–2845 (2008).
Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).
Li, X. et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl Cancer Inst. 100, 672–679 (2008).
Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009).
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).
Yilmaz, M. & Christofori, G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 28, 15–33 (2009).
Mani, S. A. et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).
Chen, Y. C. et al. Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem. Biophys. Res. Commun. 385, 307–313 (2009).
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).
Mulholland, D. J. et al. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res. 72, 1878–1889 (2012).
Morel, A. P. et al. Generation of breast cancer stem cells through epithelial–mesenchymal transition. PLoS ONE 3, e2888 (2008).
Wellner, U. et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell Biol. 11, 1487–1495 (2009).
Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29, 4741–4751 (2010).
Holohan, C., Van Schaeybroeck, S., Longley, D. B. & Johnston, P. G. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13, 714–726 (2013).
Shook, D. & Keller, R. Mechanisms, mechanics and function of epithelial–mesenchymal transitions in early development. Mech. Dev. 120, 1351–1383 (2003).
Hay, E. D. The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev. Dyn. 233, 706–720 (2005).
Dressler, G. R. The cellular basis of kidney development. Annu. Rev. Cell Dev. Biol. 22, 509–529 (2006).
Kalluri, R. & Weinberg, R. A. The basics of epithelial–mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).
Taube, J. H. et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc. Natl Acad. Sci. USA 107, 15449–15454 (2010).
Zavadil, J. & Bottinger, E. P. TGF-β and epithelial-to-mesenchymal transitions. Oncogene 24, 5764–5774 (2005).
Xu, J., Lamouille, S. & Derynck, R. TGF-β-induced epithelial to mesenchymal transition. Cell Res. 19, 156–172 (2009).
Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178–196 (2014).
Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
De Craene, B. & Berx, G. Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 13, 97–110 (2013).
Hugo, H. J. et al. Defining the E-cadherin repressor interactome in epithelial–mesenchymal transition: the PMC42 model as a case study. Cells Tissues Organs 193, 23–40 (2011).
Diaz-Lopez, A., Moreno-Bueno, G. & Cano, A. Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives. Cancer Manag. Res. 6, 205–216 (2014).
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).
Gregory, P. A. et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 10, 593–601 (2008).
Kim, N. H. et al. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial–mesenchymal transition. J. Cell Biol. 195, 417–433 (2011).
Siemens, H. et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial–mesenchymal transitions. Cell Cycle 10, 4256–4271 (2011).
Zhou, B. P. et al. Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial–mesenchymal transition. Nat. Cell Biol. 6, 931–940 (2004).
Hong, J. et al. Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res. 71, 3980–3990 (2011).
Chen, A. et al. The ubiquitin ligase Siah is a novel regulator of Zeb1 in breast cancer. Oncotarget 6, 862–873 (2015).
Thiery, J. P. Epithelial–mesenchymal transitions in development and pathologies. Curr. Opin. Cell Biol. 15, 740–746 (2003).
Carver, E. A., Jiang, R., Lan, Y., Oram, K. F. & Gridley, T. The mouse snail gene encodes a key regulator of the epithelial–mesenchymal transition. Mol. Cell. Biol. 21, 8184–8188 (2001).
Chen, Z. F. & Behringer, R. R. Twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 9, 686–699 (1995).
Van de Putte, T. et al. Mice lacking ZFHX1B, the gene that codes for Smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of Hirschsprung disease–mental retardation syndrome. Am. J. Hum. Genet. 72, 465–470 (2003).
Jiang, R., Lan, Y., Norton, C. R., Sundberg, J. P. & Gridley, T. The Slug gene is not essential for mesoderm or neural crest development in mice. Dev. Biol. 198, 277–285 (1998).
Higashi, Y. et al. Impairment of T cell development in δ EF1 mutant mice. J. Exp. Med. 185, 1467–1479 (1997).
Sosic, D., Richardson, J. A., Yu, K., Ornitz, D. M. & Olson, E. N. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-κB activity. Cell 112, 169–180 (2003).
Bain, G. et al. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell 79, 885–892 (1994).
Zhuang, Y., Soriano, P. & Weintraub, H. The helix-loop-helix gene E2A is required for B cell formation. Cell 79, 875–884 (1994).
Yao, D., Dai, C. & Peng, S. Mechanism of the mesenchymal–epithelial transition and its relationship with metastatic tumor formation. Mol. Cancer Res. 9, 1608–1620 (2011).
Gunasinghe, N. P., Wells, A., Thompson, E. W. & Hugo, H. J. Mesenchymal–epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev. 31, 469–478 (2012).
Li, R. et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 7, 51–63 (2010).
Little, M. H. & McMahon, A. P. Mammalian kidney development: principles, progress, and projections. Cold Spring Harb. Perspect. Biol. 4, a008300 (2012).
Tarin, D., Thompson, E. W. & Newgreen, D. F. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res. 65, 5996–6000 (2005).
Thompson, L., Chang, B. & Barsky, S. H. Monoclonal origins of malignant mixed tumors (carcinosarcomas). Evidence for a divergent histogenesis. Am. J. Surg. Pathol. 20, 277–285 (1996).
Mareel, M., Vleminckx, K., Vermeulen, S., Bracke, M. & Van Roy, F. E-Cadherin expression: a counterbalance for cancer cell invasion. Bull. Cancer 79, 347–355 (1992).
Birchmeier, W. & Behrens, J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim. Biophys. Acta 1198, 11–26 (1994).
Cano, A. et al. The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. 2, 76–83 (2000).
Blanco, M. J. et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21, 3241–3246 (2002).
Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).
Gravdal, K., Halvorsen, O. J., Haukaas, S. A. & Akslen, L. A. A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin. Cancer Res. 13, 7003–7011 (2007).
Soltermann, A. et al. Prognostic significance of epithelial-mesenchymal and mesenchymal–epithelial transition protein expression in non-small cell lung cancer. Clin. Cancer Res. 14, 7430–7437 (2008).
Rasheed, Z. A. et al. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J. Natl Cancer Inst. 102, 340–351 (2010).
Lee, T. K. et al. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial–mesenchymal transition. Clin. Cancer Res. 12, 5369–5376 (2006).
Spaderna, S. et al. A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology 131, 830–840 (2006).
Baumgart, E. et al. Identification and prognostic significance of an epithelial–mesenchymal transition expression profile in human bladder tumors. Clin. Cancer Res. 13, 1685–1694 (2007).
Yu, M. et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584 (2013).
Weinstein, R. S., Merk, F. B. & Alroy, J. The structure and function of intercellular junctions in cancer. Adv. Cancer Res. 23, 23–89 (1976).
Gabbert, H., Wagner, R., Moll, R. & Gerharz, C. D. Tumor dedifferentiation: an important step in tumor invasion. Clin. Exp. Metastasis 3, 257–279 (1985).
Cheung, K. J., Gabrielson, E., Werb, Z. & Ewald, A. J. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155, 1639–1651 (2013).
Mayer, B. et al. E-Cadherin expression in primary and metastatic gastric cancer: down-regulation correlates with cellular dedifferentiation and glandular disintegration. Cancer Res. 53, 1690–1695 (1993).
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, 10356–11036 (2001).
Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial–mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724 (2012).
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).
Lawson, D. A. et al. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature 526, 131–135 (2015).
Berx, G. et al. E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 13, 1919–1925 (1996).
Husemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008).
Ye, X. et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature 525, 256–260 (2015).
Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012).
Pantel, K., Alix-Panabieres, C. & Riethdorf, S. Cancer micrometastases. Nat. Rev. Clin. Oncol. 6, 339–351 (2009).
Klein, C. A. Selection and adaptation during metastatic cancer progression. Nature 501, 365–372 (2013).
Trimboli, A. J. et al. Direct evidence for epithelial–mesenchymal transitions in breast cancer. Cancer Res. 68, 937–945 (2008).
Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
Mueller, M. M. & Fusenig, N. E. Friends or foes — bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).
Ohlund, D., Elyada, E. & Tuveson, D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211, 1503–1523 (2014).
Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).
Hayward, S. W. et al. Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res. 61, 8135–8142 (2001).
Giannoni, E. et al. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial–mesenchymal transition and cancer stemness. Cancer Res. 70, 6945–6956 (2010).
Yu, Y. et al. Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF-β signalling. Br. J. Cancer 110, 724–732 (2014).
Nielsen, B. S., Sehested, M., Timshel, S., Pyke, C. & Dano, K. Messenger RNA for urokinase plasminogen activator is expressed in myofibroblasts adjacent to cancer cells in human breast cancer. Lab. Invest. 74, 168–177 (1996).
Martin, M., Pujuguet, P. & Martin, F. Role of stromal myofibroblasts infiltrating colon cancer in tumor invasion. Pathol. Res. Pract. 192, 712–717 (1996).
Nakayama, H. et al. The role of myofibroblasts at the tumor border of invasive colorectal adenocarcinomas. Jpn J. Clin. Oncol. 28, 615–620 (1998).
Sparmann, A. & Bar-Sagi, D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6, 447–458 (2004).
Yang, G. et al. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Natl Acad. Sci. USA 103, 16472–164773 (2006).
Kim, H., Choi, J. A. & Kim, J. H. Ras promotes transforming growth factor-β (TGF-β)-induced epithelial–mesenchymal transition via a leukotriene B4 receptor-2-linked cascade in mammary epithelial cells. J. Biol. Chem. 289, 22151–22160 (2014).
Wu, Y. et al. Stabilization of snail by NF-κB is required for inflammation-induced cell migration and invasion. Cancer Cell 15, 416–428 (2009).
Sullivan, N. J. et al. Interleukin-6 induces an epithelial–mesenchymal transition phenotype in human breast cancer cells. Oncogene 28, 2940–2947 (2009).
Li, Y., Wang, L., Pappan, L., Galliher-Beckley, A. & Shi, J. IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Mol. Cancer 11, 87 (2012).
Lin, E. Y., Nguyen, A. V., Russell, R. G. & Pollard, J. W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193, 727–740 (2001).
Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).
Bonde, A. K., Tischler, V., Kumar, S., Soltermann, A. & Schwendener, R. A. Intratumoral macrophages contribute to epithelial–mesenchymal transition in solid tumors. BMC Cancer 12, 35 (2012).
Su, S. et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell 25, 605–620 (2014).
Kumar, V., Patel, S., Tcyganov, E. & Gabrilovich, D. I. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37, 208–220 (2016).
Powell, D. R. & Huttenlocher, A. Neutrophils in the tumor microenvironment. Trends Immunol. 37, 41–52 (2016).
Freisinger, C. M. & Huttenlocher, A. Live imaging and gene expression analysis in zebrafish identifies a link between neutrophils and epithelial to mesenchymal transition. PLoS ONE 9, e112183 (2014).
Toh, B. et al. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol. 9, e1001162 (2011).
Krishnamachary, B. et al. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel–Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res. 66, 2725–2731 (2006).
Esteban, M. A. et al. Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res. 66, 3567–3575 (2006).
Imai, T. et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am. J. Pathol. 163, 1437–1447 (2003).
Lester, R. D., Jo, M., Montel, V., Takimoto, S. & Gonias, S. L. uPAR induces epithelial–mesenchymal transition in hypoxic breast cancer cells. J. Cell Biol. 178, 425–436 (2007).
Yang, M. H. et al. Direct regulation of TWIST by HIF-1α promotes metastasis. Nat. Cell Biol. 10, 295–305 (2008).
Thompson, E. W., Newgreen, D. F. & Tarin, D. Carcinoma invasion and metastasis: a role for epithelial–mesenchymal transition? Cancer Res. 65, 5991–5995 (2005).
Fidler, I. J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat. Rev. Cancer 3, 453–458 (2003).
Scheel, C. & Weinberg, R. A. Cancer stem cells and epithelial–mesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22, 396–403 (2012).
Chaffer, C. L. et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc. Natl Acad. Sci. USA 108, 7950–7955 (2011).
Gupta, P. B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).
Chaffer, C. L. et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154, 61–74 (2013).
Baccelli, I. & Trumpp, A. The evolving concept of cancer and metastasis stem cells. J. Cell Biol. 198, 281–293 (2012).
Waerner, T. et al. ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell 10, 227–239 (2006).
Onder, T. T. et al. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 68, 3645–3654 (2008).
Del Pozo Martin, Y. et al. Mesenchymal cancer cell-stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization. Cell Rep. 13, 2456–2469 (2015).
Barkan, D. et al. Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res. 68, 6241–6250 (2008).
Shibue, T. & Weinberg, R. A. Integrin β1-focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs. Proc. Natl Acad. Sci. USA 106, 10290–10295 (2009).
Shibue, T., Brooks, M. W. Inan, M. F., Reinhardt, F. & Weinberg, R. A. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discov. 2, 706–721 (2012).
Shibue, T., Brooks, M. W. & Weinberg, R. A. An integrin-linked machinery of cytoskeletal regulation that enables experimental tumor initiation and metastatic colonization. Cancer Cell 24, 481–498 (2013).
Fischer, K. R. et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015).
Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).
Scheel, C. et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145, 926–940 (2011).
Ni, T. et al. Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer. Nat. Cell Biol. 18, 1221–1232 (2016).
Kim, J. et al. Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity. Proc. Natl Acad. Sci. USA 109, 6124–6129 (2012).
Liu, S. et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2, 78–91 (2014).
Jolly, M. K. et al. Coupling the modules of EMT and stemness: a tunable 'stemness window' model. Oncotarget 6, 25161–25174 (2015).
Bierie, B. et al. Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells. Proc. Natl Acad. Sci. USA 114, E2337–E2346 (2017).
Al-Hajj, M., Becker, M. W., Wicha, M., Weissman, I. & Clarke, M. F. Therapeutic implications of cancer stem cells. Curr. Opin. Genet. Dev. 14, 43–47 (2004).
Lerner, C. & Harrison, D. E. 5-Fluorouracil spares hemopoietic stem cells responsible for long-term repopulation. Exp. Hematol. 18, 114–118 (1990).
Bouwens, L. & De Blay, E. Islet morphogenesis and stem cell markers in rat pancreas. J. Histochem. Cytochem. 44, 947–951 (1996).
Peters, R., Leyvraz, S. & Perey, L. Apoptotic regulation in primitive hematopoietic precursors. Blood 92, 2041–2052 (1998).
Feuerhake, F., Sigg, W., Hofter, E. A., Dimpfl, T. & Welsch, U. Immunohistochemical analysis of Bcl-2 andBax expression in relation to cell turnover and epithelial differentiation markers in the non-lactating human mammary gland epithelium. Cell Tissue Res. 299, 47–58 (2000).
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).
Potten, C. S. & Loeffler, M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110, 1001–1020 (1990).
Levina, V., Marrangoni, A. M., DeMarco, R., Gorelik, E. & Lokshin, A. E. Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS ONE 3, e3077 (2008).
Dallas, N. A. et al. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 69, 1951–1957 (2009).
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).
Kottke, T. et al. Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors. Nat. Med. 17, 854–859 (2011).
Boisgerault, N. et al. Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse. Mol. Ther. 21, 1507–1516 (2013).
Farmer, P. et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat. Med. 15, 68–74 (2009).
Byers, L. A. et al. An epithelial–mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin. Cancer Res. 19, 279–290 (2013).
Bierie, B. & Moses, H. L. Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer 6, 506–520 (2006).
Deheuninck, J. & Luo, K. Ski and SnoN, potent negative regulators of TGF-β signaling. Cell Res. 19, 47–57 (2009).
Akhurst, R. J. & Hata, A. Targeting the TGFβ signalling pathway in disease. Nat. Rev. Drug Discov. 11, 790–811 (2012).
Neuzillet, C. et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol. Ther. 147, 22–31 (2015).
Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G. F. Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol. 4, 915–925 (2003).
Gherardi, E., Birchmeier, W., Birchmeier, C. & Vande Woude, G. Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer 12, 89–103 (2012).
Scagliotti, G. V., Novello, S. & von Pawel, J. The emerging role of MET/HGF inhibitors in oncology. Cancer Treat. Rev. 39, 793–801 (2013).
Albini, A. & Sporn, M. B. The tumour microenvironment as a target for chemoprevention. Nat. Rev. Cancer 7, 139–147 (2007).
Bargagna-Mohan, P. et al. The tumor inhibitor and antiangiogenic agent withaferin A targets the intermediate filament protein vimentin. Chem. Biol. 14, 623–634 (2007).
Thaiparambil, J. T. et al. Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. Int. J. Cancer 129, 2744–2755 (2011).
Tanaka, H. et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat. Med. 16, 1414–1420 (2010).
Hafizi, S. & Dahlback, B. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev. 17, 295–304 (2006).
Gjerdrum, C. et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc. Natl Acad. Sci. USA 107, 1124–1129 (2010).
Byers, L. et al. A phase I/II and pharmacokinetic study of BGB324, a selective AXL inhibitor as monotherapy and in combination with erlotinib in patients with advanced non-small cell lung cancer (NSCLC). Eur. J. Cancer 69, S18–S19 (2017).
Gupta, P. B. et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138, 645–659 (2009).
Tam, W. L. et al. Protein kinase C α is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell 24, 347–364 (2013).
Tallman, M. S. & Altman, J. K. How I treat acute promyelocytic leukemia. Blood 114, 5126–5135 (2009).
Pattabiraman, D. R. et al. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Science 351, aad3680 (2016).
Marcucci, F., Stassi, G. & De Maria, R. Epithelial–mesenchymal transition: a new target in anticancer drug discovery. Nat. Rev. Drug Discov. 15, 311–325 (2016).
Schmidt, J. M. et al. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. Cell Rep. 10, 131–139 (2015).
Marjanovic, N. D., Weinberg, R. A. & Chaffer, C. L. Cell plasticity and heterogeneity in cancer. Clin. Chem. 59, 168–179 (2013).
Clark, A. G. & Vignjevic, D. M. Modes of cancer cell invasion and the role of the microenvironment. Curr. Opin. Cell Biol. 36, 13–22 (2015).
Hennessy, B. T. et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69, 4116–4124 (2009).
Shimono, Y. et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138, 592–603 (2009).
Leung, E. L. H. et al. Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS ONE 5, e14062 (2010).
Pirozzi, G. et al. Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PLoS ONE 6, e21548 (2011).
Kong, D. J. et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS ONE 5, e12445 (2010).
Wu, W. S. et al. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123, 641–653 (2005).
Wu, D. W. et al. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction. Oncogene 34, 3882–3883 (2015).
Vega, S. et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 18, 1131–1143 (2004).
Escriva, M. et al. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol. Cell. Biol. 28, 1528–1540 (2008).
Lu, M. et al. E-cadherin couples death receptors to the cytoskeleton to regulate apoptosis. Mol. Cell 54, 987–998 (2014).
Saxena, M., Stephens, M. A., Pathak, H. & Rangarajan, A. Transcription factors that mediate epithelial–mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death Dis. 2, e179 (2011).
Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl Med. 3, 75ra26 (2011).
Zhang, Z. et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat. Genet. 44, 852–860 (2012).
Kudo-Saito, C., Shirako, H., Takeuchi, T. & Kawakami, Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 15, 195–206 (2009).