Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? (original) (raw)

• Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
  Article CAS PubMed Google Scholar
• Tsao, H., Atkins, M. B. & Sober, A. J. Management of cutaneous melanoma. N. Engl. J. Med. 351, 998–1012 (2004).
  Article CAS PubMed Google Scholar
• Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Flaherty, K. T. et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367, 107–114 (2012).
  Article CAS PubMed Google Scholar
• Tsao, H., Chin, L., Garraway, L. A. & Fisher, D. E. Melanoma: from mutations to medicine. Genes Dev. 26, 1131–1155 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).
  Article CAS PubMed Google Scholar
• Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).
  Article CAS PubMed Google Scholar
• Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010).
  Article CAS PubMed Google Scholar
• Marusyk, A., Almendro, V. & Polyak, K. Intra-tumour heterogeneity: a looking glass for cancer? Nature Rev. Cancer 12, 323–334 (2012).
  Article CAS Google Scholar
• Merlo, L. M., Pepper, J. W., Reid, B. J. & Maley, C. C. Cancer as an evolutionary and ecological process. Nature Rev. Cancer 6, 924–935 (2006).
  Article CAS Google Scholar
• Gerlinger, M. & Swanton, C. How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine. Br. J. Cancer 103, 1139–1143 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Gillies, R. J., Verduzco, D. & Gatenby, R. A. Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nature Rev. Cancer 12, 487–493 (2012).
  Article CAS Google Scholar
• Zhou, B. B. et al. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nature Rev. Drug Discov. 8, 806–823 (2009).
  Article CAS Google Scholar
• Frank, N. Y., Schatton, T. & Frank, M. H. The therapeutic promise of the cancer stem cell concept. J. Clin. Invest. 120, 41–50 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Clevers, H. The cancer stem cell: premises, promises and challenges. Nature Med. 17, 313–319 (2011).
  Article CAS PubMed Google Scholar
• Magee, J. A., Piskounova, E. & Morrison, S. J. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21, 283–296 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ossowski, L. & Aguirre-Ghiso, J. A. Dormancy of metastatic melanoma. Pigment Cell Melanoma Res. 23, 41–56 (2010).
  Article PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Baylin, S. B. Resistance, epigenetics and the cancer ecosystem. Nature Med. 17, 288–289 (2011).
  Article CAS PubMed Google Scholar
• Wilting, R. H. & Dannenberg, J. H. Epigenetic mech-anisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Drug Resist. Updat. 15, 21–38 (2012).
  Article CAS PubMed Google Scholar
• Borst, P. Cancer drug pan-resistance: pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what? Open. Biol. 2, 120066 (2012).
  Google Scholar
• Egeblad, M., Nakasone, E. S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Correia, A. L. & Bissell, M. J. The tumor microenvironment is a dominant force in multidrug resistance. Drug Resist. Updat. 15, 39–49 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Meads, M. B., Gatenby, R. A. & Dalton, W. S. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nature Rev. Cancer 9, 665–674 (2009).
  Article CAS Google Scholar
• Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
  Article CAS PubMed Google Scholar
• Gottesman, M. M., Fojo, T. & Bates, S. E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nature Rev. Cancer 2, 48–58 (2002).
  Article CAS Google Scholar
• Chabner, B. A. & Roberts, T. G. Jr. Timeline: Chemotherapy and the war on cancer. Nature Rev. Cancer 5, 65–72 (2005).
  Article CAS Google Scholar
• Wang, T. L. et al. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc. Natl Acad. Sci. USA 101, 3089–3094 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Huang, S. et al. MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. Cell 151, 937–950 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Gilbert, L. A. & Hemann, M. T. DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355–366 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gilbert, L. A. & Hemann, M. T. Chemotherapeutic resistance: surviving stressful situations. Cancer Res. 71, 5062–5066 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Shree, T. et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 25, 2465–2479 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Nakasone, E. S. et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21, 488–503 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Denardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Acharyya, S. et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Kioi, M. et al. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120, 694–705 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Bruchard, M. et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nature Med. 19, 57–64 (2013).
  Article CAS PubMed Google Scholar
• Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Med. 2, 561–566 (1996).
  Article CAS PubMed Google Scholar
• Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001).
  Article CAS PubMed Google Scholar
• Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876–880 (2001).
  Article CAS PubMed Google Scholar
• Soverini, S. et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118, 1208–1215 (2011).
  Article CAS PubMed Google Scholar
• Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).
  Article CAS PubMed Google Scholar
• Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011).
  Article PubMed PubMed Central Google Scholar
• Ercan, D. et al. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene 29, 2346–2356 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Rosell, R. et al. Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin. Cancer Res. 17, 1160–1168 (2011).
  Article CAS PubMed Google Scholar
• Su, K. Y. et al. Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J. Clin. Oncol. 30, 433–440 (2012).
  Article CAS PubMed Google Scholar
• Prahallad, A. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).
  Article CAS PubMed Google Scholar
• Corcoran, R. B. et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2, 227–235 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• O'Hare, T., Zabriskie, M. S., Eiring, A. M. & Deininger, M. W. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nature Rev. Cancer 12, 513–526 (2012).
  Article CAS Google Scholar
• Whittaker, S. et al. Gatekeeper mutations mediate resistance to BRAF-targeted therapies. Sci. Transl. Med. 2, 35ra41 (2010).
  Article PubMed CAS Google Scholar
• Poulikakos, P. I. & Rosen, N. Mutant BRAF melanomas--dependence and resistance. Cancer Cell 19, 11–15 (2011).
  Article CAS PubMed Google Scholar
• Johannessen, C. M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968–972 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Villanueva, J. et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18, 683–695 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Das, T. M. et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494, 251–255 (2013).
  Article CAS Google Scholar
• Wilson, T. R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Takayama, H., La Rochelle, W. J., Anver, M., Bockman, D. E. & Merlino, G. Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development. Proc. Natl Acad. Sci. USA 93, 5866–5871 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Takayama, H. et al. Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proc. Natl Acad. Sci. USA 94, 701–706 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, W. et al. Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin. Cancer Res. 15, 6630–6638 (2009).
  Article CAS PubMed Google Scholar
• Yano, S. et al. Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort. J. Thorac. Oncol. 6, 2011–2017 (2011).
  Article PubMed Google Scholar
• Blattman, J. N. & Greenberg, P. D. Cancer immunotherapy: a treatment for the masses. Science 305, 200–205 (2004).
  Article CAS PubMed Google Scholar
• Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Rosenberg, S. A. Progress in human tumour immunology and immunotherapy. Nature 411, 380–384 (2001).
  Article CAS PubMed Google Scholar
• Boon, T., Coulie, P. G., Van den Eynde, B. J. & van der, B. P. Human T cell responses against melanoma. Annu. Rev. Immunol. 24, 175–208 (2006).
  Article CAS PubMed Google Scholar
• Atkins, M. B. et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17, 2105–2116 (1999).
  Article CAS PubMed Google Scholar
• Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nature Med. 10, 909–915 (2004).
  Article CAS PubMed Google Scholar
• Dudley, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Yee, C. et al. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc. Natl Acad. Sci. USA 99, 16168–16173 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Dudley, M. E. et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J. Clin. Oncol. 23, 2346–2357 (2005).
  Article CAS PubMed Google Scholar
• Mackensen, A. et al. Phase I study of adoptive T-cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma. J. Clin. Oncol. 24, 5060–5069 (2006).
  Article CAS PubMed Google Scholar
• Chapuis, A. G. et al. Transferred melanoma-specific CD8+ T cells persist, mediate tumor regression, and acquire central memory phenotype. Proc. Natl Acad. Sci. USA 109, 4592–4597 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nature Rev. Immunol. 12, 269–281 (2012).
  Article CAS Google Scholar
• Khong, H. T. & Restifo, N. P. Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nature Immunol. 3, 999–1005 (2002).
  Article CAS Google Scholar
• Restifo, N. P. et al. Loss of functional beta 2-microglobulin in metastatic elanomas from five patients receiving immunotherapy. J. Natl Cancer Inst. 88, 100–108 (1996).
  Article CAS PubMed Google Scholar
• Jager, E. et al. Immunoselection in vivo: independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma. Int. J. Cancer. 71, 142–147 (1997).
  Article CAS PubMed Google Scholar
• Khong, H. T., Wang, Q. J. & Rosenberg, S. A. Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression. J. Immunother. 27, 184–190 (2004).
  Article PubMed PubMed Central Google Scholar
• Garrido, F. Cabrera, T., & Aptsiauri, N. “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int. J. Cancer. 127, 249–256 (2010).
  CAS PubMed Google Scholar
• Rosenberg, S. A. et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. J. Immunol. 175, 6169–6176 (2005).
  Article CAS PubMed Google Scholar
• Appay, V. et al. New generation vaccine induces effective melanoma-specific CD8+ T cells in the circulation but not in the tumor site. J. Immunol. 177, 1670–1678 (2006).
  Article CAS PubMed Google Scholar
• Baitsch, L. et al. Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J. Clin. Invest. 121, 2350–2360 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Wherry, E. J. T cell exhaustion. Nature Immunol. 12, 492–499 (2011).
  Article CAS Google Scholar
• Soudja, S. M. et al. Tumor-initiated inflammation overrides protective adaptive immunity in an induced melanoma model in mice. Cancer Res. 70, 3515–3525 (2010).
  Article CAS PubMed Google Scholar
• Meyer, C. et al. Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc. Natl Acad. Sci. USA 108, 17111–17116 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Rev. Cancer 5, 263–274 (2005).
  Article CAS Google Scholar
• Rabinovich, G. A., Gabrilovich, D. & Sotomayor, E. M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Mellor, A. L. & Munn, D. H. Creating immune privilege: active local suppression that benefits friends, but protects foes. Nature Rev. Immunol. 8, 74–80 (2008).
  Article CAS Google Scholar
• Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
  Article CAS PubMed Google Scholar
• Kohlmeyer, J. et al. Complete regression of advanced primary and metastatic mouse melanomas following combination chemoimmunotherapy. Cancer Res. 69, 6265–6274 (2009).
  Article CAS PubMed Google Scholar
• Landsberg, J. et al. Autochthonous primary and metastatic melanomas in Hgf-Cdk4 R24C mice evade T-cell-mediated immune surveillance. Pigment Cell Melanoma Res. 23, 649–660 (2010).
  Article CAS PubMed Google Scholar
• Landsberg, J. et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 490, 412–416 (2012).
  Article CAS PubMed Google Scholar
• Hendrix, M. J., Seftor, E. A., Hess, A. R. & Seftor, R. E. Molecular plasticity of human melanoma cells. Oncogene 22, 3070–3075 (2003).
  Article CAS PubMed Google Scholar
• White, R. M. & Zon, L. I. Melanocytes in development, regeneration, and cancer. Cell Stem Cell. 3, 242–252 (2008).
  Article CAS PubMed Google Scholar
• Bailey, C. M., Morrison, J. A. & Kulesa, P. M. Melanoma revives an embryonic igration program to promote plasticity and invasion. Pigment Cell Melanoma Res. 25, 573–583 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Quintana, E. et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 18, 510–523 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Boiko, A. D. et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 466, 133–137 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Civenni, G. et al. Human CD271-positive melanoma stem cells associated with metastasis establish tumor heterogeneity and long-term growth. Cancer Res. 71, 3098–3109 (2011).
  Article CAS PubMed Google Scholar
• Hoek, K. S. et al. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res. 68, 650–656 (2008).
  Article CAS PubMed Google Scholar
• Pinner, S. et al. Intravital imaging reveals transient changes in pigment production and Brn2 expression during metastatic melanoma dissemination. Cancer Res. 69, 7969–7977 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Roesch, A. et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141, 583–594 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Javelaud, D. et al. GLI2 and M-MITF transcription factors control exclusive gene expression programs and inversely regulate invasion in human melanoma cells. Pigment Cell Melanoma Res. 24, 932–943 (2011).
  Article CAS PubMed Google Scholar
• Cheli, Y. et al. Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny. Oncogene 30, 2307–2318 (2011).
  Article CAS PubMed Google Scholar
• Widmer, D. S. et al. Systematic classification of melanoma cells by phenotype-specific gene expression mapping. Pigment Cell Melanoma Res. 25, 343–353 (2012).
  Article CAS PubMed Google Scholar
• Knutson, K. L. et al. Immunoediting of cancers may lead to epithelial to mesenchymal transition. J. Immunol. 177, 1526–1533 (2006).
  Article CAS PubMed Google Scholar
• Santisteban, M. et al. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res. 69, 2887–2895 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Asiedu, M. K., Ingle, J. N., Behrens, M. D., Radisky, D. C. & Knutson, K. L. TGFβ/TNFα-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype. Cancer Res. 71, 4707–4719 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).
  Article CAS PubMed Google Scholar
• Gupta, P. B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).
  Article CAS PubMed Google Scholar
• Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kulbe, H. et al. A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment. Cancer Res. 72, 66–75 (2012).
  Article CAS PubMed Google Scholar
• Gray-Schopfer, V. C., Karasarides, M., Hayward, R. & Marais, R. Tumor necrosis factor-alpha blocks apoptosis in melanoma cells when BRAF signaling is inhibited. Cancer Res. 67, 122–129 (2007).
  Article CAS PubMed Google Scholar
• Yao, Z. et al. TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc. Natl Acad. Sci. USA 107, 15535–15540 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Li, G. et al. Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene 20, 8125–8135 (2001).
  Article CAS PubMed Google Scholar
• Koefinger, P. et al. The cadherin switch in melanoma instigated by HGF is mediated through epithelial-mesenchymal transition regulators. Pigment Cell Melanoma Res. 24, 382–385 (2011).
  Article CAS PubMed Google Scholar
• Witta, S. E. et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res. 66, 944–950 (2006).
  Article CAS PubMed Google Scholar
• Creighton, C. J. et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl Acad. Sci. USA 106, 13820–13825 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Cheng, W. Y., Kandel, J. J., Yamashiro, D. J., Canoll, P. & Anastassiou, D. A multi-cancer mesenchymal transition gene expression signature is associated with prolonged time to recurrence in glioblastoma. PLoS ONE 7, e34705 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, Z. et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature Genet. 44, 852–860 (2012).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kanno, Y., Vahedi, G., Hirahara, K., Singleton, K. & O'Shea, J. J. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu. Rev. Immunol. 30, 707–731 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Taube, J. M. et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 4, 127ra37 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Pilon-Thomas, S., Mackay, A., Vohra, N. & Mule, J. J. Blockade of programmed death ligand 1 enhances the therapeutic efficacy of combination immunotherapy against melanoma. J. Immunol. 184, 3442–3449 (2010).
  Article CAS PubMed Google Scholar
• Peng, W. et al. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-gamma inducible chemokines. Cancer Res. 72, 5209–5218 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Zaidi, M. R. et al. Interferon-gamma links ultraviolet radiation to melanomagenesis in mice. Nature 469, 548–553 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Motz, G. T. & Coukos, G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nature Rev. Immunol. 11, 702–711 (2011).
  Article CAS Google Scholar
• Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011).
  Article CAS PubMed Google Scholar
• Hansen, W. et al. Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. J. Exp. Med. 209, 2001–2016 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Calcinotto, A. et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 72, 2746–2756 (2012).
  Article CAS PubMed Google Scholar
• Bakhoum, S. F. & Compton, D. A. Chromosomal instability and cancer: a complex relationship with therapeutic potential. J. Clin. Invest. 122, 1138–1143 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Miller, B. E., Miller, F. R., Leith, J. & Heppner, G. H. Growth interaction in vivo between tumor subpopulations derived from a single mouse mammary tumor. Cancer Res. 40, 3977–3981 (1980).
  CAS PubMed Google Scholar
• Axelrod, R., Axelrod, D. E. & Pienta, K. J. Evolution of cooperation among tumor cells. Proc. Natl Acad. Sci. USA 103, 13474–13479 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Calbo, J. et al. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer. Cancer Cell 19, 244–256 (2011).
  Article CAS PubMed Google Scholar
• Mullighan, C. G. et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 322, 1377–1380 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Anderson, K. et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469, 356–361 (2011).
  Article CAS PubMed Google Scholar
• Notta, F. et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 469, 362–367 (2011).
  Article CAS PubMed Google Scholar
• 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
• Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Acar, M., Mettetal, J. T. & van, O.A. Stochastic switching as a survival strategy in fluctuating environments. Nature Genet. 40, 471–475 (2008).
  Article CAS PubMed Google Scholar
• Brogan, J. et al. Imaging molecular pathways: reporter genes. Radiat. Res. 177, 508–513 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Glunde, K. & Bhujwalla, Z. M. Metabolic tumor imaging using magnetic resonance spectroscopy. Semin. Oncol. 38, 26–41 (2011).
  Article PubMed PubMed Central Google Scholar
• Kobus, D., Giesen, Y., Ullrich, R., Backes, H. & Neumaier, B. A fully automated two-step synthesis of an 18F-labelled tyrosine kinase inhibitor for EGFR kinase activity imaging in tumors. Appl. Radiat. Isot. 67, 1977–1984 (2009).
  Article CAS PubMed Google Scholar
• Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Waddington, C. H. The Strategy of the Genes: a Discussion of Some Aspects of Theoretical Biology (Taylor & Francis, 1957).
  Google Scholar
• Huang, S., Ernberg, I. & Kauffman, S. Cancer attractors: a systems view of tumors from a gene network dynamics and developmental perspective. Semin. Cell Dev. Biol. 20, 869–876 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Chang, H. H., Hemberg, M., Barahona, M., Ingber, D. E. & Huang, S. Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature 453, 544–547 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Eldar, A. & Elowitz, M. B. Functional roles for noise in genetic circuits. Nature 467, 167–173 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Hoek, K. S. & Goding, C. R. Cancer stem cells versus phenotype-switching in melanoma. Pigment Cell Melanoma Res. 23, 746–759 (2010).
  Article CAS PubMed Google Scholar
• Bozic, I. et al. Accumulation of driver and passenger mutations during tumor progression. Proc. Natl Acad. Sci. USA 107, 18545–18550 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Antal, T. & Krapivsky, P. L. Exact solution of a two-type branching process: models of tumor progression. J. Statist. Mechanics. Theor. Exp. 08, P08018 (2011).
  Google Scholar
• Leder, K., Holland, E. C. & Michor, F. The therapeutic implications of plasticity of the cancer stem cell phenotype. PLoS ONE 5, e14366 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Bolker, B. & Pacala, S. W. Using moment equations to understand stochastically driven spatial pattern formation in ecological systems. Theor. Popul. Biol. 52, 179–197 (1997).
  Article CAS PubMed Google Scholar
• Law, R. & Dieckmann, U. in The Geometry of Ecological Interactions: Simplifying Spatial Complexity (eds Dieckmann, U., Law, R. & Metz, J. A. J.) 252–270 (Cambridge University Press, 2000).
  Book Google Scholar
• Etheridge, A. M. Survival and extinction in a locally regulated population. Ann. Appl. Probab. 14, 188–214 (2004).
  Article Google Scholar
• Fournier, N. & Méléard, S. A microscopic probabilistic description of a locally regulated population and macroscopic approximation. Ann. Appl. Probab. 14, 1880–1919 (2004).
  Article Google Scholar
• Champagnat, N. A microscopic interpretation for adaptive dynamics trait substitution sequence models. Stoch. Proc. Appl. 116, 127–1160 (2006).
  Google Scholar
• Champagnat, N. & Lambert, A. Evolution of discrete populations and the canonical diffusion of adaptive dynamics. Ann. Appl. Probab. 17, 102–155 (2007).
  Article Google Scholar
• Champagnat, N. & Méléard, S. Polymorphic evolution sequence and evolutionary branching. Probab. Theor. Relat. Field. 151, 45–94 (2011).
  Article Google Scholar
• Clayton, A. & Evans, S. N. Mutation-selection balance with recombination: convergence to equilibrium for polynomial selection costs. SIAM J. Appl. Math 69, 1772–1792 (2009).
  Article Google Scholar
• Bovier, A. & Wang, S. D. Multi-time scales in adaptive dynamics: microscopic interpretation of a trait substitution tree model. Preprint at http://arxiv.org/abs/1207.4690 (2012).
• Schroeder, T. Long-term single-cell imaging of mammalian stem cells. Nature Methods 8, S30–S35 (2011).
  Article CAS PubMed Google Scholar
• Kastenmuller, W., Torabi-Parizi, P., Subramanian, N., Lammermann, T. & Germain, R. N. A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread. Cell 150, 1235–1248 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Kreso, A. et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 339, 543–548 (2013).
  Article CAS PubMed Google Scholar
• Shintani, Y. et al. Epithelial to mesenchymal transition is a determinant of sensitivity to chemoradiotherapy in non-small cell lung cancer. Ann. Thorac. Surg. 92, 1794–1804 (2011).
  Article PubMed Google Scholar
• Uramoto, H., Shimokawa, H., Hanagiri, T., Kuwano, M. & Ono, M. Expression of selected gene for acquired drug resistance to EGFR-TKI in lung adenocarcinoma. Lung Cancer 73, 361–365 (2011).
  Article PubMed Google Scholar
• Lee, M. J. et al. Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 149, 780–794 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Klein, C. A. & Holzel, D. Systemic cancer progression and tumor dormancy: mathematical models meet single cell genomics. Cell Cycle 5, 1788–1798 (2006).
  Article CAS PubMed Google Scholar
• Haeno, H. et al. Computational modeling of pancreatic cancer reveals kinetics of metastasis suggesting optimum treatment strategies. Cell 148, 362–375 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Iwami, S., Haeno, H. & Michor, F. A race between tumor immunoescape and genome maintenance selects for optimum levels of (epi)genetic instability. PLoS. Comput. Biol. 8, e1002370 (2012).
  Article CAS PubMed PubMed Central Google Scholar