Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy

Abstract

The MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it initiates and sustains neoplastic transformation when genetically altered (‘oncogene addiction’) and fosters cancer cell survival and tumour dissemination when transcriptionally activated in the context of an adaptive response to adverse microenvironmental conditions (‘oncogene expedience’). Moreover, MET is an intrinsic modulator of the self-renewal and clonogenic ability of cancer stem cells (‘oncogene inherence’). Here, we provide the latest findings on MET function in cancer by focusing on newly identified genetic abnormalities in tumour cells and recently described non-mutational MET activities in stromal cells and cancer stem cells. We discuss how MET drives cancer clonal evolution and progression towards metastasis, both ab initio and under therapeutic pressure. We then elaborate on the use of MET inhibitors in the clinic with a critical appraisal of failures and successes. Ultimately, we advocate a rationale to improve the outcome of anti-MET therapies on the basis of thorough consideration of the entire spectrum of MET-mediated biological responses, which implicates adequate patient stratification, meaningful biomarkers and appropriate clinical end points.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: MET structural alterations and oncogene addiction.
Fig. 2: MET oncogene expedience.
Fig. 3: Stromal HGF protects cancer cells from targeted therapy.
Fig. 4: The MET oncogene in cancer stem cells: a paradigm of inherence.

Similar content being viewed by others

References

  1. Trusolino, L., Bertotti, A. & Comoglio, P. M. MET signalling: principles and functions in development, organ regeneration and cancer. Nat. Rev. Mol. Cell Biol. 11, 834–848 (2010).

    Article  PubMed  CAS  Google Scholar 

  2. Trusolino, L. & Comoglio, P. M. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat. Rev. Cancer 2, 289–300 (2002).

    Article  PubMed  CAS  Google Scholar 

  3. Boccaccio, C. & Comoglio, P. M. Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat. Rev. Cancer 6, 637–645 (2006).

    Article  PubMed  CAS  Google Scholar 

  4. Christofori, G. New signals from the invasive front. Nature 441, 444–450 (2006).

    Article  PubMed  CAS  Google Scholar 

  5. Ye, X. & Weinberg, R. A. Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 25, 675–686 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Bottaro, D. P. et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251, 802–804 (1991).

    Article  PubMed  CAS  Google Scholar 

  7. Naldini, L. et al. Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J. 10, 2867–2878 (1991).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Nakamura, T., Nawa, K. & Ichihara, A. Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem. Biophys. Res. Commun. 122, 1450–1459 (1984).

    Article  PubMed  CAS  Google Scholar 

  9. Stoker, M., Gherardi, E., Perryman, M. & Gray, J. Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327, 239–242 (1987).

    Article  PubMed  CAS  Google Scholar 

  10. Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G. F. Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol. 4, 915–925 (2003).

    Article  PubMed  CAS  Google Scholar 

  11. Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Shibue, T. & Weinberg, R. A. E. M. T. CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 14, 611–629 (2017). This is a comprehensive Review discussing the relationship between the stemness and invasive phenotypes in cancer and its therapeutic implications.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Scheel, C., Onder, T., Karnoub, A. & Weinberg, R. A. Adaptation versus selection: the origins of metastatic behavior. Cancer Res. 67, 11476–11479 (2007).

    Article  PubMed  CAS  Google Scholar 

  14. Di Renzo, M. F. et al. Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene 19, 1547–1555 (2000).

    Article  PubMed  CAS  Google Scholar 

  15. Comoglio, P. M., Giordano, S. & Trusolino, L. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat. Rev. Drug Discov. 7, 504–516 (2008).

    Article  PubMed  CAS  Google Scholar 

  16. Gherardi, E., Birchmeier, W., Birchmeier, C. & Vande, W. G. Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer 12, 89–103 (2012).

    Article  PubMed  CAS  Google Scholar 

  17. Corso, S. et al. Silencing the MET oncogene leads to regression of experimental tumors and metastases. Oncogene 27, 684–693 (2008).

    Article  PubMed  CAS  Google Scholar 

  18. Pennacchietti, S. et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3, 347–361 (2003).

    Article  PubMed  Google Scholar 

  19. Boccaccio, C., Gaudino, G., Gambarotta, G., Galimi, F. & Comoglio, P. M. Hepatocyte growth factor (HGF) receptor expression is inducible and is part of the delayed-early response to HGF. J. Biol. Chem. 269, 12846–12851 (1994).

    PubMed  CAS  Google Scholar 

  20. Bhowmick, N. A., Neilson, E. G. & Moses, H. L. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. Michieli, P. et al. Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell 6, 61–73 (2004).

    Article  PubMed  CAS  Google Scholar 

  23. Hayward, N. K. et al. Whole-genome landscapes of major melanoma subtypes. Nature 545, 175–180 (2017).

    Article  PubMed  CAS  Google Scholar 

  24. Ponzetto, C. et al. c-Met is amplified but not mutated in a cell line with an activated met tyrosine kinase. Oncogene 6, 553–559 (1991).

    PubMed  CAS  Google Scholar 

  25. Jeffers, M. et al. Activating mutations for the met tyrosine kinase receptor in human cancer. Proc. Natl Acad. Sci. USA 94, 11445–11450 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Snuderl, M. et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20, 810–817 (2011). This study provides evidence that, in individual glioblastomas, MET, EGFR and PDGFR genes are amplified in different cells in a mutually exclusive fashion, implying that inhibition of each individual receptor alone can result in a selective advantage for subclones harbouring amplification of another.

    Article  PubMed  CAS  Google Scholar 

  27. Turke, A. B. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17, 77–88 (2010). This study shows that subclones harbouring MET amplification pre-exist in lung cancers with EGFR mutations and are positively selected by treatment with EGFR inhibitors.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Arteaga, C. L. & Engelman, J. A. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25, 282–303 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).

    Article  PubMed  CAS  Google Scholar 

  30. Bardelli, A. et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 3, 658–673 (2013). This study shows that MET amplification is a mechanism of resistance to anti-EGFR therapy in metastatic colorectal cancer, as an alternative to mutations in KRAS.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Bertotti, A. et al. The genomic landscape of response to EGFR blockade in colorectal cancer. Nature 526, 263–267 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Pietrantonio, F. et al. MET-driven resistance to dual EGFR and BRAF blockade may be overcome by switching from EGFR to MET inhibition in BRAF-mutated colorectal cancer. Cancer Discov. 6, 963–971 (2016).

    Article  PubMed  CAS  Google Scholar 

  33. Cepero, V. MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors. Cancer Res. 70, 7580–7590 (2010).

    Article  PubMed  CAS  Google Scholar 

  34. Henry, R. E. et al. Acquired savolitinib resistance in non-small cell lung cancer arises via multiple mechanisms that converge on MET-independent mTOR and MYC activation. Oncotarget 7, 57651–57670 (2016).

    PubMed  PubMed Central  Google Scholar 

  35. Kwak, E. L. et al. Molecular heterogeneity and receptor coamplification drive resistance to targeted therapy in MET-amplified esophagogastric cancer. Cancer Discov. 5, 1271–1281 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Bahcall, M. et al. Acquired MET D1228V mutation and resistance to MET inhibition in lung cancer. Cancer Discov. 6, 1334–1341 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Gandino, L., Longati, P., Medico, E., Prat, M. & Comoglio, P. M. Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase. J. Biol. Chem. 269, 1815–1820 (1994).

    PubMed  CAS  Google Scholar 

  38. Nakayama, M. et al. Met/HGF receptor activation is regulated by juxtamembrane Ser985 phosphorylation in hepatocytes. Cytokine 62, 446–452 (2013).

    Article  PubMed  CAS  Google Scholar 

  39. Peschard, P. et al. Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Mol. Cell 8, 995–1004 (2001).

    Article  PubMed  CAS  Google Scholar 

  40. Petrelli, A. et al. The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Nature 416, 187–190 (2002).

    Article  PubMed  CAS  Google Scholar 

  41. Weidner, K. M., Sachs, M., Riethmacher, D. & Birchmeier, W. Mutation of juxtamembrane tyrosine residue 1001 suppresses loss-of- function mutations of the met receptor in epithelial cells. Proc. Natl Acad. Sci. USA 92, 2597–2601 (1995).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Ma, P. C. et al. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res. 63, 6272–6281 (2003).

    PubMed  CAS  Google Scholar 

  43. Lee, C. C. & Yamada, K. M. Identification of a novel type of alternative splicing of a tyrosine kinase receptor. Juxtamembrane deletion of the c-met protein kinase C serine phosphorylation regulatory site. J. Biol. Chem. 269, 19457–19461 (1994).

    PubMed  CAS  Google Scholar 

  44. Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015).

    Article  PubMed  CAS  Google Scholar 

  45. Ma, P. C. et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res. 65, 1479–1488 (2005).

    Article  PubMed  CAS  Google Scholar 

  46. Kong-Beltran, M. et al. Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res. 66, 283–289 (2006).

    Article  PubMed  CAS  Google Scholar 

  47. Vigna, E., Gramaglia, D., Longati, P., Bardelli, A. & Comoglio, P. M. Loss of the exon encoding the juxtamembrane domain is essential for the oncogenic activation of TPR-MET. Oncogene 18, 4275–4281 (1999).

    Article  PubMed  CAS  Google Scholar 

  48. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

    Article  CAS  Google Scholar 

  49. Awad, M. M. et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J. Clin. Oncol. 34, 721–730 (2016).

    Article  PubMed  CAS  Google Scholar 

  50. Tong, J. H. et al. MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis. Clin. Cancer Res. 22, 3048–3056 (2016).

    Article  PubMed  CAS  Google Scholar 

  51. Liu, X. et al. Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET Gene Mutations. J. Clin. Oncol. 34, 794–802 (2016).

    Article  PubMed  CAS  Google Scholar 

  52. Paik, P. K. et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 5, 842–849 (2015). References 44 and 52 are the first studies to systematically analyse the prevalence of MET exon 14 deletion across tumour types, finding the highest frequency in lung cancer. These two studies also show that MET inhibition induces durable responses in patients harbouring such an alteration.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Lee, J. et al. Gastrointestinal malignancies harbor actionable MET exon 14 deletions. Oncotarget 6, 28211–28222 (2015).

    PubMed  PubMed Central  Google Scholar 

  54. Soman, N. R., Correa, P., Ruiz, B. A. & Wogan, G. N. The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Proc. Natl Acad. Sci. USA 88, 4892–4896 (1991).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Stransky, N., Cerami, E., Schalm, S., Kim, J. L. & Lengauer, C. The landscape of kinase fusions in cancer. Nat. Commun. 5, 4846 (2014).

    Article  PubMed  CAS  Google Scholar 

  56. Bao, Z. S. et al. RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas. Genome Res. 24, 1765–1773 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. International Cancer Genome Consortium PedBrain Tumor Project. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma. Nat. Med. 22, 1314–1320 (2016).

    Article  CAS  Google Scholar 

  58. Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Navis, A. C. et al. Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein. Acta Neuropathol. 130, 131–144 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Gambarotta, G., Pistoi, S., Giordano, S., Comoglio, P. M. & Santoro, C. Structure and inducible regulation of the human MET promoter. J. Biol. Chem. 269, 12852–12857 (1994).

    PubMed  CAS  Google Scholar 

  61. Chen, Q., Seol, D. W., Carr, B. & Zarnegar, R. Co-expression and regulation of Met and Ron proto-oncogenes in human hepatocellular carcinoma tissues and cell lines. Hepatology 26, 59–66 (1997).

    PubMed  CAS  Google Scholar 

  62. Hwang, C. I. et al. Wild-type p53 controls cell motility and invasion by dual regulation of MET expression. Proc. Natl Acad. Sci. USA 108, 14240–14245 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Epstein, J. A., Shapiro, D. N., Cheng, J., Lam, P. Y. & Maas, R. L. Pax3 modulates expression of the c-Met receptor during limb muscle development. Proc. Natl Acad. Sci. USA 93, 4213–4218 (1996).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Kubic, J. D., Little, E. C., Lui, J. W., Iizuka, T. & Lang, D. PAX3 and ETS1 synergistically activate MET expression in melanoma cells. Oncogene 34, 4964–4974 (2015).

    Article  PubMed  CAS  Google Scholar 

  65. Gambarotta, G. et al. Ets up-regulates MET transcription. Oncogene 13, 1911–1917 (1996).

    PubMed  CAS  Google Scholar 

  66. Finkbeiner, M. R. et al. Profiling YB-1 target genes uncovers a new mechanism for MET receptor regulation in normal and malignant human mammary cells. Oncogene 28, 1421–1431 (2009).

    Article  PubMed  CAS  Google Scholar 

  67. De Bacco, F. et al. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J. Natl Cancer Inst. 103, 645–661 (2011).

    Article  PubMed  CAS  Google Scholar 

  68. Zarnegar, R. Regulation of HGF and HGFR gene expression. EXS 74, 33–49 (1995).

    PubMed  CAS  Google Scholar 

  69. Bigatto, V. et al. TNF-alpha promotes invasive growth through the MET signaling pathway. Mol. Oncol. 9, 377–388 (2015).

    Article  PubMed  CAS  Google Scholar 

  70. Sennino, B., Ishiguro-Oonuma, T., Schriver, B. J., Christensen, J. G. & McDonald, D. M. Inhibition of c-Met reduces lymphatic metastasis in RIP-Tag2 transgenic mice. Cancer Res. 73, 3692–3703 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Pàez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Sennino, B. et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2, 270–287 (2012). This study shows that anti-angiogenic therapy can promote invasion and metastasis, an outcome that can be prevented by concomitant MET inhibition.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Rigamonti, N. et al. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 8, 696–706 (2014).

    Article  PubMed  CAS  Google Scholar 

  75. Bill, R. et al. Nintedanib is a highly effective therapeutic for neuroendocrine carcinoma of the pancreas (PNET) in the Rip1Tag2 transgenic mouse model. Clin. Cancer Res. 21, 4856–4867 (2015).

    Article  PubMed  CAS  Google Scholar 

  76. Jubb, A. M., Oates, A. J., Holden, S. & Koeppen, H. Predicting benefit from anti-angiogenic agents in malignancy. Nat. Rev. Cancer 6, 626–635 (2006).

    Article  PubMed  CAS  Google Scholar 

  77. McIntyre, A. & Harris, A. L. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality. EMBO Mol. Med. 7, 368–379 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Lu, K. V. et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22, 21–35 (2012). This study provides evidence that VEGF inhibition can disrupt a physical interaction between VEGFR2 and MET and enable pro-invasive activities in tumour cells.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. De Bacco, F. et al. MET inhibition overcomes radiation resistance of glioblastoma stem-like cells. EMBO Mol. Med. 8, 550–568 (2016). This study shows, in a preclinical model, that MET inhibition can circumvent the recognized radioresistance of glioblastoma stem cells by enhancing the DDR.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Du, Y. et al. Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors. Nat. Med. 22, 194–201 (2016). This study shows that MET inhibitors suppress a mechanism of resistance to PARP inhibitors and provides preclinical evidence for combination therapy in breast and ovarian cancer.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. De Palma, M., Biziato, D. & Petrova, T. V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17, 457–474 (2017).

    Article  PubMed  CAS  Google Scholar 

  82. McCourt, M., Wang, J. H., Sookhai, S. & Redmond, H. P. Activated human neutrophils release hepatocyte growth factor/scatter factor. Eur. J. Surg. Oncol. 27, 396–403 (2001).

    Article  PubMed  CAS  Google Scholar 

  83. Galimi, F. et al. Hepatocyte growth factor is a regulator of monocyte-macrophage function. J. Immunol. 166, 1241–1247 (2001).

    Article  PubMed  CAS  Google Scholar 

  84. Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Wilson, T. R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Harbinski, F. et al. Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth. Cancer Discov. 2, 948–959 (2012). References 84–86 highlight the ability of HGF present in the microenvironment to protect cancer cells from the actions of BRAF or tyrosine kinase inhibitors.

    Article  PubMed  CAS  Google Scholar 

  87. Yano, S. et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 68, 9479–9487 (2008).

    Article  PubMed  CAS  Google Scholar 

  88. Pennacchietti, S. et al. Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs. Cancer Res. 74, 6598–6609 (2014).

    Article  PubMed  CAS  Google Scholar 

  89. Nakamura, T., Matsumoto, K., Kiritoshi, A. & Tano, Y. Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: in vitro analysis of tumor-stromal interactions. Cancer Res. 57, 3305–3313 (1997).

    PubMed  CAS  Google Scholar 

  90. Kawaguchi, M. & Kataoka, H. Mechanisms of hepatocyte growth factor activation in cancer tissues. Cancers 6, 1890–1904 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Zarnegar, R. & Michalopoulos, G. K. The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J. Cell Biol. 129, 1177–1180 (1995).

    Article  PubMed  CAS  Google Scholar 

  92. Ilangumaran, S., Villalobos-Hernandez, A., Bobbala, D. & Ramanathan, S. The hepatocyte growth factor (HGF)-MET receptor tyrosine kinase signaling pathway: Diverse roles in modulating immune cell functions. Cytokine 82, 125–139 (2016).

    Article  PubMed  CAS  Google Scholar 

  93. Flaquer, M. et al. Hepatocyte growth factor gene therapy enhances infiltration of macrophages and may induce kidney repair in db/db mice as a model of diabetes. Diabetologia 55, 2059–2068 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Molnarfi, N., Benkhoucha, M., Bjarnadóttir, K., Juillard, C. & Lalive, P. H. Interferon-β induces hepatocyte growth factor in monocytes of multiple sclerosis patients. PLoS ONE 7, e49882 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Coudriet, G. M., He, J., Trucco, M., Mars, W. M. & Piganelli, J. D. Hepatocyte growth factor modulates interleukin-6 production in bone marrow derived macrophages: implications for inflammatory mediated diseases. PLoS ONE 5, e15384 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).

    Article  PubMed  CAS  Google Scholar 

  97. Tu, H. et al. CXCR4 and SDF-1 production are stimulated by hepatocyte growth factor and promote glioma cell invasion. Onkologie 32, 331–336 (2009).

    Article  PubMed  CAS  Google Scholar 

  98. Holland, J. D. et al. Combined Wnt/β-catenin, Met, and CXCL12/CXCR4 signals characterize basal breast cancer and predict disease outcome. Cell Rep. 5, 1214–1227 (2013).

    Article  PubMed  CAS  Google Scholar 

  99. Sánchez-Martín, L. et al. The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression. Blood 117, 88–97 (2011).

    Article  PubMed  CAS  Google Scholar 

  100. Balkwill, F. Cancer and the chemokine network. Nat. Rev. Cancer 4, 540–550 (2004).

    Article  PubMed  CAS  Google Scholar 

  101. Baek, J. H., Birchmeier, C., Zenke, M. & Hieronymus, T. The HGF receptor/Met tyrosine kinase is a key regulator of dendritic cell migration in skin immunity. J. Immunol. 189, 1699–1707 (2012).

    Article  PubMed  CAS  Google Scholar 

  102. Okunishi, K. et al. A novel role of hepatocyte growth factor as an immune regulator through suppressing dendritic cell function. J. Immunol. 175, 4745–4753 (2005).

    Article  PubMed  CAS  Google Scholar 

  103. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 5, 263–274 (2005).

    Article  PubMed  CAS  Google Scholar 

  104. Yamaura, K. et al. Suppression of acute and chronic rejection by hepatocyte growth factor in a murine model of cardiac transplantation: induction of tolerance and prevention of cardiac allograft vasculopathy. Circulation 110, 1650–1657 (2004).

    Article  PubMed  CAS  Google Scholar 

  105. Futamatsu, H. et al. Hepatocyte growth factor ameliorates the progression of experimental autoimmune myocarditis: a potential role for induction of T helper 2 cytokines. Circ. Res. 96, 823–830 (2005).

    Article  PubMed  CAS  Google Scholar 

  106. Benkhoucha, M. et al. Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells. J. Immunol. 193, 2743–2752 (2014).

    Article  PubMed  CAS  Google Scholar 

  107. Singhal, E. & Sen, P. Hepatocyte growth factor-induced c-Src-phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway inhibits dendritic cell activation by blocking IκB kinase activity. Int. J. Biochem. Cell Biol. 43, 1134–1146 (2011).

    Article  PubMed  CAS  Google Scholar 

  108. Singhal, E., Kumar, P. & Sen, P. A novel role for Bruton’s tyrosine kinase in hepatocyte growth factor-mediated immunoregulation of dendritic cells. J. Biol. Chem. 286, 32054–32063 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Motz, G. T. & Coukos, G. Deciphering and reversing tumor immune suppression. Immunity 39, 61–73 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Finisguerra, V. et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature 522, 349–353 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Mishalian, I. et al. Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression. Cancer Immunol. Immunother. 62, 1745–1756 (2013).

    Article  PubMed  CAS  Google Scholar 

  112. Glodde, N. et al. Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy. Immunity 47, 789–802.e789 (2017).

    Article  PubMed  CAS  Google Scholar 

  113. Théry, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2, 569–579 (2002).

    Article  PubMed  CAS  Google Scholar 

  114. Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. White, A. C. & Lowry, W. E. Refining the role for adult stem cells as cancer cells of origin. Trends Cell Biol. 25, 11–20 (2015).

    Article  PubMed  CAS  Google Scholar 

  116. Ishikawa, T. et al. Hepatocyte growth factor/c-met signaling is required for stem-cell-mediated liver regeneration in mice. Hepatology 55, 1215–1226 (2012).

    Article  PubMed  CAS  Google Scholar 

  117. Kitade, M. et al. Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling. Genes Dev. 27, 1706–1717 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Gastaldi, S. et al. Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer. Oncogene 32, 1428–1440 (2013).

    Article  PubMed  CAS  Google Scholar 

  119. Nicoleau, C. et al. Endogenous hepatocyte growth factor is a niche signal for subventricular zone neural stem cell amplification and self-renewal. Stem Cells 27, 408–419 (2009).

    Article  PubMed  CAS  Google Scholar 

  120. Joosten, S. P. J. et al. MET Signaling Mediates Intestinal Crypt-Villus Development, Regeneration, and Adenoma Formation and Is Promoted by Stem Cell CD44 Isoforms. Gastroenterology 153, 1040–1053.e4 (2017).

    Article  PubMed  CAS  Google Scholar 

  121. Luraghi, P. et al. MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors. Cancer Res. 74, 1857–1869 (2014).

    Article  PubMed  CAS  Google Scholar 

  122. Li, C. et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology 141, 2218–2227 (2011).

    Article  PubMed  CAS  Google Scholar 

  123. De Bacco, F. et al. The MET Oncogene Is a Functional Marker of a Glioblastoma Stem Cell Subtype. Cancer Res. 72, 4537–4550 (2012).

    Article  PubMed  CAS  Google Scholar 

  124. Li, Y. et al. c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc. Natl Acad. Sci. USA 108, 9951–9956 (2011). This study shows that MET sustains the stem cell phenotype in glioblastoma through induction of reprogramming transcription factors.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Joo, K. M. et al. MET signaling regulates glioblastoma stem cells. Cancer Res. 72, 3828–3838 (2012).

    Article  PubMed  CAS  Google Scholar 

  126. Tamase, A. et al. Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin. Proc. Natl Acad. Sci. USA 106, 17163–17168 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Kentsis, A. et al. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nat. Med. 18, 1118–1122 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Gohda, E. et al. Biological and immunological properties of human hepatocyte growth factor from plasma of patients with fulminant hepatic failure. Biochim. Biophys. Acta 1053, 21–26 (1990).

    Article  PubMed  CAS  Google Scholar 

  129. Kopp, J. L., Grompe, M. & Sander, M. Stem cells versus plasticity in liver and pancreas regeneration. Nat. Cell Biol. 18, 238–245 (2016).

    Article  PubMed  CAS  Google Scholar 

  130. Schmidt, C. et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature 373, 699–702 (1995).

    Article  PubMed  CAS  Google Scholar 

  131. Suzuki, A. et al. Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver. J. Cell Biol. 156, 173–184 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Duncan, A. W., Dorrell, C. & Grompe, M. Stem cells and liver regeneration. Gastroenterology 137, 466–481 (2009).

    Article  PubMed  Google Scholar 

  133. Visvader, J. E. & Stingl, J. Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes Dev. 28, 1143–1158 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Graveel, C. R. et al. Met induces diverse mammary carcinomas in mice and is associated with human basal breast cancer. Proc. Natl Acad. Sci. USA 106, 12909–12914 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Charafe-Jauffret, E. et al. Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 25, 2273–2284 (2006).

    Article  PubMed  CAS  Google Scholar 

  136. Molyneux, G. et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7, 403–417 (2010).

    Article  PubMed  CAS  Google Scholar 

  137. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  140. Vermeulen, L. et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc. Natl Acad. Sci. USA 105, 13427–13432 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  142. Luraghi, P. et al. A molecularly annotated model of patient-derived colon cancer stem-like cells to assess genetic and non-genetic mechanisms of resistance to anti-EGFR therapy. Clin. Cancer Res. 24, 807–820 (2018).

  143. Date, S. & Sato, T. Mini-gut organoids: reconstitution of the stem cell niche. Annu. Rev. Cell Dev. Biol. 31, 269–289 (2015).

    Article  PubMed  CAS  Google Scholar 

  144. Zeilstra, J. et al. Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res. 68, 3655–3661 (2008).

    Article  PubMed  CAS  Google Scholar 

  145. Zoller, M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat. Rev. Cancer 11, 254–267 (2011).

    Article  PubMed  CAS  Google Scholar 

  146. Orian-Rousseau, V., Chen, L., Sleeman, J. P., Herrlich, P. & Ponta, H. CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev. 16, 3074–3086 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Todaro, M. et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 14, 342–356 (2014).

    Article  PubMed  CAS  Google Scholar 

  148. Alcantara Llaguno, S. R. & Parada, L. F. Cell of origin of glioma: biological and clinical implications. Br. J. Cancer 115, 1445–1450 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Anido, J. et al. TGF-beta receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell 18, 655–668 (2010).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  152. McDermott, U. et al. Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc. Natl Acad. Sci. USA 104, 19936–19941 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Benvenuti, S. et al. An ‘in-cell trial’ to assess the efficacy of a monovalent anti-MET antibody as monotherapy and in association with standard cytotoxics. Mol. Oncol. 8, 378–388 (2014).

    Article  PubMed  CAS  Google Scholar 

  154. Lennerz, J. K. et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J. Clin. Oncol. 29, 4803–4810 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Spigel, D. R. et al. Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J. Clin. Oncol. 35, 412–420 (2017).

    Article  PubMed  CAS  Google Scholar 

  156. Scagliotti, G. et al. Phase III multinational, randomized, double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus erlotinib alone in previously treated patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer. J. Clin. Oncol. 33, 2667–2674 (2015).

    Article  PubMed  CAS  Google Scholar 

  157. Basilico, C. et al. Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET. Clin. Cancer Res. 19, 2381–2392 (2013).

    Article  PubMed  CAS  Google Scholar 

  158. Calles, A. et al. Tivantinib (ARQ 197) efficacy is independent of MET inhibition in non-small-cell lung cancer cell lines. Mol. Oncol. 9, 260–269 (2015).

    Article  PubMed  CAS  Google Scholar 

  159. 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  PubMed  CAS  Google Scholar 

  160. Garassino, M. C. et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 14, 981–988 (2013).

    Article  PubMed  CAS  Google Scholar 

  161. Surati, M., Patel, P., Peterson, A. & Salgia, R. Role of MetMAb (OA-5D5) in c-MET active lung malignancies. Expert Opin. Biol. Ther. 11, 1655–1662 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Catenacci, D. V. T. et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 18, 1467–1482 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  163. Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014).

    Article  PubMed  CAS  Google Scholar 

  164. Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02323126 (2017).

  166. Tabassum, D. P. & Polyak, K. Tumorigenesis: it takes a village. Nat. Rev. Cancer 15, 473–483 (2015).

    Article  PubMed  CAS  Google Scholar 

  167. Siravegna, G., Marsoni, S., Siena, S. & Bardelli, A. Integrating liquid biopsies into the management of cancer. Nat. Rev. Clin. Oncol. 14, 116–120 (2017).

    Article  CAS  Google Scholar 

  168. Wan, J. C. et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat. Rev. Cancer 17, 223–238 (2017).

    Article  PubMed  CAS  Google Scholar 

  169. Camidge, D. R. et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC) [abstract]. J. Clin. Oncol. 32(Suppl.), 8001 (2014).

    Google Scholar 

  170. Crosetto, N., Bienko, M. & van Oudenaarden, A. Spatially resolved transcriptomics and beyond. Nat. Rev. Genet. 16, 57–66 (2015).

    Article  PubMed  CAS  Google Scholar 

  171. Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Mazzone, M. et al. An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice. J. Clin. Invest. 114, 1418–1432 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Ponzetto, C. et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 77, 261–271 (1994).

    Article  PubMed  CAS  Google Scholar 

  174. Boccaccio, C. et al. Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature 391, 285–288 (1998).

    Article  PubMed  CAS  Google Scholar 

  175. Schaeper, U. et al. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. J. Cell Biol. 149, 1419–1432 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Weidner, K. M. et al. Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 384, 173–176 (1996).

    Article  PubMed  CAS  Google Scholar 

  177. Benvenuti, S. et al. Ron kinase transphosphorylation sustains MET oncogene addiction. Cancer Res. 71, 1945–1955 (2011).

    Article  PubMed  CAS  Google Scholar 

  178. Viticchiè, G. & Muller, P. A. J. c-Met and other cell surface molecules: interaction, activation and functional consequences. Biomedicines 3, 46–70 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Gentile, A., Lazzari, L., Benvenuti, S., Trusolino, L. & Comoglio, P. M. Ror1 is a pseudokinase that is crucial for Met-driven tumorigenesis. Cancer Res. 71, 3132–3141 (2011).

    Article  PubMed  CAS  Google Scholar 

  180. Orian-Rousseau, V. CD44 acts as a signaling platform controlling tumor progression and metastasis. Front. Immunol. 6, 154 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Giordano, S. et al. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat. Cell Biol. 4, 720–724 (2002).

    Article  PubMed  CAS  Google Scholar 

  182. Trusolino, L., Bertotti, A. & Comoglio, P. M. A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Cell 107, 643–654 (2001).

    Article  PubMed  CAS  Google Scholar 

  183. Franco, M. et al. The tetraspanin CD151 is required for Met-dependent signaling and tumor cell growth. J. Biol. Chem. 285, 38756–38764 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Thorpe, L. M., Yuzugullu, H. & Zhao, J. J. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer 15, 7–24 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Ménard, L., Parker, P. J. & Kermorgant, S. Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways. Nat. Commun. 5, 3907 (2014).

    Article  PubMed  CAS  Google Scholar 

  186. Varadhachary, G. R. & Raber, M. N. Cancer of unknown primary site. N. Engl. J. Med. 371, 757–765 (2014).

    Article  PubMed  CAS  Google Scholar 

  187. Jeffers, M. et al. The mutationally activated Met receptor mediates motility and metastasis. Proc. Natl Acad. Sci. USA 95, 14417–14422 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Rong, S., Segal, S., Anver, M., Resau, J. H. & Vande, W. G. F. Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proc. Natl Acad. Sci. USA 91, 4731–4735 (1994).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Jeffers, M., Rong, S., Anver, M. & Vande, W. G. F. Autocrine hepatocyte growth factor/scatter factor-Met signaling induces transformation and the invasive/metastastic phenotype in C127 cells. Oncogene 13, 853–856 (1996).

    PubMed  CAS  Google Scholar 

  190. Gallego, M. I., Bierie, B. & Hennighausen, L. Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways. Oncogene 22, 8498–8508 (2003).

    Article  PubMed  CAS  Google Scholar 

  191. Meiners, S., Brinkmann, V., Naundorf, H. & Birchmeier, W. Role of morphogenetic factors in metastasis of mammary carcinoma cells. Oncogene 16, 9–20 (1998).

    Article  PubMed  CAS  Google Scholar 

  192. Stella, G. M. et al. MET mutations in cancers of unknown primary origin (CUPs). Hum. Mutat. 32, 44–50 (2011).

    Article  PubMed  CAS  Google Scholar 

  193. Gherardi, E. et al. Functional map and domain structure of MET, the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor. Proc. Natl Acad. Sci. USA 100, 12039–12044 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Stella, G. M. et al. MET mutations are associated with aggressive and radioresistant brain metastatic non-small-cell lung cancer. Neuro Oncol. 18, 598–599 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Lamszus, K., Laterra, J., Westphal, M. & Rosen, E. M. Scatter factor/hepatocyte growth factor (SF/HGF) content and function in human gliomas. Int. J. Dev. Neurosci. 17, 517–530 (1999).

    Article  PubMed  CAS  Google Scholar 

  196. Chaft, J. E. et al. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin. Cancer Res. 17, 6298–6303 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Kuriyama, Y. et al. Disease flare after discontinuation of crizotinib in anaplastic lymphoma kinase-positive lung cancer. Case Rep. Oncol. 6, 430–433 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Pupo, E. et al. Rebound effects caused by withdrawal of MET kinase inhibitor are quenched by a MET therapeutic antibody. Cancer Res. 76, 5019–5029 (2016).

    Article  PubMed  CAS  Google Scholar 

  199. Sangwan, V. et al. Regulation of the Met receptor-tyrosine kinase by the protein-tyrosine phosphatase 1B and T-cell phosphatase. J. Biol. Chem. 283, 34374–34383 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Stamos, J., Lazarus, R. A., Yao, X., Kirchhofer, D. & Wiesmann, C. Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor. EMBO J. 23, 2325–2335 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Gherardi, E. et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc. Natl Acad. Sci. USA 103, 4046–4051 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Basilico, C., Arnesano, A., Galluzzo, M., Comoglio, P. M. & Michieli, P. A high affinity hepatocyte growth factor-binding site in the immunoglobulin-like region of Met. J. Biol. Chem. 283, 21267–21277 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Basilico, C. et al. Four individually druggable MET hotspots mediate HGF-driven tumor progression. J. Clin. Invest. 124, 3172–3186 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. DiCara, D. M. et al. Characterization and structural determination of a new anti-MET function-blocking antibody with binding epitope distinct from the ligand binding domain. Sci. Rep. 7, 9000 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Park, M. et al. Mechanism of met oncogene activation. Cell 45, 895–904 (1986).

    Article  PubMed  CAS  Google Scholar 

  206. Ohuchida, K. et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 64, 3215–3222 (2004).

    Article  PubMed  CAS  Google Scholar 

  207. Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. DeNardo, D. G., Andreu, P. & Coussens, L. M. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev. 29, 309–316 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).

    Article  PubMed  CAS  Google Scholar 

  210. Coffelt, S. B., Wellenstein, M. D. & de Visser, K. E. Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).

    Article  PubMed  CAS  Google Scholar 

  211. D’Arcangelo, M. & Cappuzzo, F. Focus on the potential role of ficlatuzumab in the treatment of non-small cell lung cancer. Biologics 7, 61–68 (2013).

    PubMed  PubMed Central  Google Scholar 

  212. Liu, L. et al. LY2875358, a neutralizing and internalizing anti-MET bivalent antibody, inhibits HGF-dependent and HGF-independent MET activation and tumor growth. Clin. Cancer Res. 20, 6059–6070 (2014).

    Article  PubMed  CAS  Google Scholar 

  213. Hultberg, A. et al. Depleting MET-expressing tumor cells by ADCC provides a therapeutic advantage over inhibiting HGF/MET signaling. Cancer Res. 75, 3373–3383 (2015).

    Article  PubMed  CAS  Google Scholar 

  214. Lee, B. S. et al. Met degradation by SAIT301, a Met monoclonal antibody, reduces the invasion and migration of nasopharyngeal cancer cells via inhibition of EGR-1 expression. Cell Death Dis. 5, e1159 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Lee, J. M. et al. Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody. Oncogene 33, 34–43 (2014).

    Article  PubMed  CAS  Google Scholar 

  216. Waqar, S. N., Morgensztern, D. & Sehn, J. MET mutation associated with responsiveness to crizotinib. J. Thorac. Oncol. 10, e29–e31 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Mendenhall, M. A. & Goldman, J. W. MET-Mutated NSCLC with Major Response to Crizotinib. J. Thorac. Oncol. 10, e33–e34 (2015).

    Article  PubMed  Google Scholar 

  218. Mahjoubi, L., Gazzah, A., Besse, B., Lacroix, L. & Soria, J. C. A never-smoker lung adenocarcinoma patient with a MET exon 14 mutation (D1028N) and a rapid partial response after crizotinib. Invest. New Drugs 34, 397–398 (2016).

    Article  PubMed  CAS  Google Scholar 

  219. Chi, A. S. et al. Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor. J. Clin. Oncol. 30, e30–e33 (2012).

    Article  PubMed  Google Scholar 

  220. Shah, M. A. et al. Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS ONE 8, e54014 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. Sequist, L. V. et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J. Clin. Oncol. 29, 3307–3315 (2011).

    Article  PubMed  CAS  Google Scholar 

  222. Yoshioka, H. et al. A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study). Ann. Oncol. 26, 2066–2072 (2015).

    Article  PubMed  CAS  Google Scholar 

  223. Schuler, M. H. et al. Phase (Ph) I study of the safety and efficacy of the cMET inhibitor capmatinib (INC280) in patients (pts) with advanced cMET + non-small cell lung cancer (NSCLC). J. Clin. Oncol. 34, 9067–9067 (2016).

    Article  Google Scholar 

  224. Wu, Y.-L. et al. Phase (Ph) II safety and efficacy results of a single-arm ph ib/II study of capmatinib (INC280) + gefitinib in patients (pts) with EGFR-mutated (mut), cMET-positive (cMET+) non-small cell lung cancer (NSCLC). J. Clin. Oncol. 34, 9020–9020 (2016).

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank J. M. Hughes for clinical trial database mining, L. Lanzetti for micrographs and M. Milan for scrutiny of MET mutations. The authors also thank A. Cignetto, D. Gramaglia and F. Natale for excellent assistance. Work in the authors’ laboratories is supported by the Italian Association for Cancer Research (‘Special Program Molecular Clinical Oncology 5 × 1000, N. 9970’ and investigator grants N. 15572 to P.M.C., N. 18532 to L.T. and N. 15709 and N. 19933 to C.B.); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS (5 × 1000 Italian Ministry of Health 2011 and 2014); Italian Ministry of Health (Ricerca Corrente); Transcan, TACTIC; and Comitato per Albi98.

Author information

Authors and Affiliations

Authors

Contributions

P.M.C., L.T. and C.B. contributed equally to writing and reviewing the manuscript.

Corresponding author

Correspondence to Paolo M. Comoglio.

Ethics declarations

Competing interests

P.M.C. is co-founder and scientific adviser of Octimet Oncology NV and Metis Precision Medicine B-Corp. C.B. and L.T. declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Reviewer information

Nature Reviews Cancer thanks G. Vande Woude, K. Matsumoto and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Related links

Candiolo Cancer Institute: http://www.ircc.it/

COSMIC catalogue of human mutations in cancer: http://cancer.sanger.ac.uk/cosmic

Report from Aveo Pharmaceuticals Inc.: https://www.sec.gov/Archives/edgar/data/1325879/000119312516706645/d249918d8k.htm

US National Institutes of Health — ClinicalTrials.gov: https://clinicaltrials.gov/

Electronic supplementary material

Glossary

Lung sarcomatoid tumours

A poorly differentiated non-small-cell lung carcinoma that contains a component of sarcoma-like cells (that is, cells that display traits of mesenchymal differentiation).

Interstitial pressure

The pressure of fluid that flows out of capillaries and fills the space between the vascular system and cells.

Progression-free survival

(PFS). The time elapsed between the initiation of treatment and the onset of disease progression; measured both during and after therapy.

Overall survival

(OS). The time elapsed between the initiation of treatment and the death of the patient.

Matrix metalloproteinases

(MMPs). Zinc-dependent proteolytic enzymes secreted by cancer cells and stromal cells; these proteases degrade extracellular matrix (ECM) components, which facilitates cancer cell invasion, and cleave cell membrane-bound or ECM-associated precursor forms of many growth factors, thereby activating them and increasing their bioavailability in the tumour microenvironment.

Exosomes

Small extracellular vesicles secreted by multiple cell types that can be internalized by other cells. The transfer of the exosomal cargo (RNAs and proteins) may induce functional modifications in the recipient cells.

Cholangiocarcinomas

A type of cancer arising in the epithelial lining of biliary ducts.

Liquid biopsies

The sampling and analysis of nucleic acids or other circulating tumour-derived materials (including cancer cells and exosomes) present in biological fluids.

Array comparative genomic hybridization

A molecular cytogenetic technique that utilizes competitive hybridization of differently labelled probes to compare gene copy number differences between two genomes.

In situ hybridization

A cytogenetic method that uses DNA or RNA probes to visualize complementary DNA or RNA sequences in tissue sections.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Comoglio, P.M., Trusolino, L. & Boccaccio, C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat Rev Cancer 18, 341–358 (2018). https://doi.org/10.1038/s41568-018-0002-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-018-0002-y

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer