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The Hippo pathway and human cancer

Key Points

  • The Hippo pathway is an evolutionarily conserved regulator of tissue growth.

  • The Hippo pathway controls multiple cellular functions that are central to tumorigenesis, including proliferation and apoptosis.

  • Hippo pathway mutations in mice and flies give rise to tumours.

  • Hippo pathway activity seems to be frequently deregulated in different human cancers but most Hippo pathway genes are not commonly mutated.

  • Molecular events such as sensitivity to the mechanical properties of tumours and crosstalk with other cancer pathways might cause Hippo pathway deregulation in human cancers.

  • Hippo pathway therapeutics and new avenues to modulate pathway activity are beginning to emerge.

Abstract

The Hippo pathway controls organ size in diverse species, whereas pathway deregulation can induce tumours in model organisms and occurs in a broad range of human carcinomas, including lung, colorectal, ovarian and liver cancer. Despite this, somatic or germline mutations in Hippo pathway genes are uncommon, with only the upstream pathway gene neurofibromin 2 (NF2) recognized as a bona fide tumour suppressor gene. In this Review, we appraise the evidence for the Hippo pathway as a cancer signalling network, and discuss cancer-relevant biological functions, potential mechanisms by which Hippo pathway activity is altered in cancer and emerging therapeutic strategies.

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Figure 1: Schematic representation of the Drosophila melanogaster Hippo pathway.
Figure 2: Schematic representation of the human Hippo pathway.
Figure 3: Biological functions of the Hippo pathway that are relevant to cancer.
Figure 4: Network-level regulation of the Hippo pathway.

References

  1. Tapon, N. et al. salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467–478 (2002). The discovery of salvador and its functional link to warts outlined the existence of a new growth control pathway in D. melanogaster , known most commonly as the Hippo pathway. This paper also provided the first evidence that the Hippo pathway is perturbed in human cancer.

    Article  CAS  PubMed  Google Scholar 

  2. Justice, R. W., Zilian, O., Woods, D. F., Noll, M. & Bryant, P. J. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 9, 534–546 (1995).

    CAS  PubMed  Google Scholar 

  3. Xu, T., Wang, W., Zhang, S., Stewart, R. A. & Yu, W. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053–1063 (1995).

    CAS  PubMed  Google Scholar 

  4. Halder, G. & Johnson, R. L. Hippo signaling: growth control and beyond. Development 138, 9–22 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Harvey, K. & Tapon, N. The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network. Nature Rev. Cancer 7, 182–191 (2007).

    CAS  Google Scholar 

  6. Harvey, K. F., Pfleger, C. M. & Hariharan, I. K. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114, 457–467 (2003).

    CAS  PubMed  Google Scholar 

  7. Udan, R. S., Kango-Singh, M., Nolo, R., Tao, C. & Halder, G. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nature Cell Biol. 5, 914–920 (2003).

    CAS  PubMed  Google Scholar 

  8. Pantalacci, S., Tapon, N. & Leopold, P. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nature Cell Biol. 5, 921–927 (2003).

    CAS  PubMed  Google Scholar 

  9. Wu, S., Huang, J., Dong, J. & Pan, D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114, 445–456 (2003).

    CAS  PubMed  Google Scholar 

  10. Kango-Singh, M. et al. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129, 5719–5730 (2002).

    CAS  PubMed  Google Scholar 

  11. Huang, J., Wu, S., Barrera, J., Matthews, K. & Pan, D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 122, 421–434 (2005). This paper described the identification of the YKI transcriptional regulator as the crucial downstream target of the D. melanogaster Hippo pathway.

    CAS  PubMed  Google Scholar 

  12. Zhao, B. et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21, 2747–2761 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Dong, J. et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130, 1120–1133 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hong, W. & Guan, K. L. The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin. Cell Dev. Biol. 23, 785–793 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Grusche, F. A., Richardson, H. E. & Harvey, K. F. Upstream regulation of the hippo size control pathway. Curr. Biol. 20, R574–R582 (2010).

    CAS  PubMed  Google Scholar 

  16. Cordenonsi, M. et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147, 759–772 (2011).

    CAS  PubMed  Google Scholar 

  17. Grzeschik, N. A., Parsons, L. M., Allott, M. L., Harvey, K. F. & Richardson, H. E. Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr. Biol. 20, 573–581 (2010).

    CAS  PubMed  Google Scholar 

  18. Robinson, B. S., Huang, J., Hong, Y. & Moberg, K. H. Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein expanded. Curr. Biol. 20, 582–590 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ling, C. et al. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc. Natl Acad. Sci. USA 107, 10532–10537 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen, C. L. et al. The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc. Natl Acad. Sci. USA 107, 15810–15815 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Varelas, X. et al. The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. Dev. Cell 19, 831–844 (2010).

    CAS  PubMed  Google Scholar 

  22. Zhao, M., Szafranski, P., Hall, C. A. & Goode, S. Basolateral junctions utilize warts signaling to control epithelial-mesenchymal transition and proliferation crucial for migration and invasion of Drosophila ovarian epithelial cells. Genetics 178, 1947–1971 (2008). This paper, together with references 17–21, discovered regulatory links between ABCPs and the Hippo pathway.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Yu, F. X. et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150, 780–791 (2012). This report, defining GPCRs as upstream regulators of the Hippo pathway, greatly increased the understanding of how mammalian Hippo pathway activity is controlled.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bennett, F. C. & Harvey, K. F. Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. Curr. Biol. 16, 2101–2110 (2006).

    CAS  PubMed  Google Scholar 

  25. Willecke, M. et al. The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size. Curr. Biol. 16, 2090–2100 (2006).

    CAS  PubMed  Google Scholar 

  26. Silva, E., Tsatskis, Y., Gardano, L., Tapon, N. & McNeill, H. The tumor-suppressor gene fat controls tissue growth upstream of expanded in the hippo signaling pathway. Curr. Biol. 16, 2081–2089 (2006).

    CAS  PubMed  Google Scholar 

  27. Cho, E. et al. Delineation of a Fat tumor suppressor pathway. Nature Genet. 38, 1142–1150 (2006).

    CAS  PubMed  Google Scholar 

  28. Camargo, F. D. et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Biol. 17, 2054–2060 (2007). This paper, together with references 12 and 13, showed that Hippo pathway signalling and function is conserved between D. melanogaster and mammals, and provided initial evidence that Hippo pathway activity is frequently disrupted in human carcinomas.

    CAS  PubMed  Google Scholar 

  29. Schlegelmilch, K. et al. Yap1 acts downstream of α-catenin to control epidermal proliferation. Cell 144, 782–795 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    CAS  PubMed  Google Scholar 

  32. Tschop, K. et al. A kinase shRNA screen links LATS2 and the pRB tumor suppressor. Genes Dev. 25, 814–830 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Aylon, Y. et al. A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization. Genes Dev. 20, 2687–2700 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Overholtzer, M. et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc. Natl Acad. Sci. USA 103, 12405–12410 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhao, B. et al. Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev. 26, 54–68 (2012).

    PubMed  PubMed Central  Google Scholar 

  36. Zhang, X. et al. The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene 30, 2810–2822 (2011).

    CAS  PubMed  Google Scholar 

  37. Izzo, J. G. et al. Pretherapy nuclear factor-κB status, chemoradiation resistance, and metastatic progression in esophageal carcinoma. Mol. Cancer Ther. 5, 2844–2850 (2006).

    CAS  PubMed  Google Scholar 

  38. Gautam, A. & Bepler, G. Suppression of lung tumor formation by the regulatory subunit of ribonucleotide reductase. Cancer Res. 66, 6497–6502 (2006).

    CAS  PubMed  Google Scholar 

  39. Valent, P. et al. Cancer stem cell definitions and terminology: the devil is in the details. Nature Rev. Cancer 12, 767–775 (2012).

    CAS  Google Scholar 

  40. Gatenby, R. A. A change of strategy in the war on cancer. Nature 459, 508–509 (2009).

    CAS  PubMed  Google Scholar 

  41. Morata, G. & Ripoll, P. Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev. Biol. 42, 211–221 (1975).

    CAS  PubMed  Google Scholar 

  42. de Beco, S., Ziosi, M. & Johnston, L. A. New frontiers in cell competition. Dev. Dyn. 241, 831–841 (2012).

    PubMed  PubMed Central  Google Scholar 

  43. Davidson, J. D. et al. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res. 64, 3761–3766 (2004).

    CAS  PubMed  Google Scholar 

  44. Ramalho-Santos, M. Yoon, S., Matsuzaki, Y., Mulligan, R. C. & Melton, D. A. “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science 298, 597–600 (2002).

    CAS  PubMed  Google Scholar 

  45. Steinhardt, A. A. et al. Expression of Yes-associated protein in common solid tumors. Hum. Pathol. 39, 1582–1589 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lian, I. et al. The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev. 24, 1106–1118 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Varelas, X. et al. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nature Cell Biol. 10, 837–848 (2008).

    CAS  PubMed  Google Scholar 

  48. Hong, J. H. et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309, 1074–1078 (2005).

    CAS  PubMed  Google Scholar 

  49. Schroeder, M. C. & Halder, G. Regulation of the Hippo pathway by cell architecture and mechanical signals. Semin. Cell Dev. Biol. 23, 803–811 (2012).

    CAS  PubMed  Google Scholar 

  50. Wang, Y. Wnt/Planar cell polarity signaling: a new paradigm for cancer therapy. Mol. Cancer Ther. 8, 2103–2109 (2009).

    CAS  PubMed  Google Scholar 

  51. Martin-Belmonte, F. & Perez-Moreno, M. Epithelial cell polarity, stem cells and cancer. Nature Rev. Cancer 12, 23–38 (2012).

    CAS  Google Scholar 

  52. Humbert, P. O. et al. Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module. Oncogene 27, 6888–6907 (2008).

    CAS  PubMed  Google Scholar 

  53. Guilford, P. et al. E-cadherin germline mutations in familial gastric cancer. Nature 392, 402–405 (1998).

    CAS  PubMed  Google Scholar 

  54. Kim, N. G., Koh, E., Chen, X. & Gumbiner, B. M. E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc. Natl Acad. Sci. USA 108, 11930–11935 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Holley, R. W. Control of growth of mammalian cells in cell culture. Nature 258, 487–490 (1975).

    CAS  PubMed  Google Scholar 

  56. Lallemand, D., Curto, M., Saotome, I., Giovannini, M. & McClatchey, A. I. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev. 17, 1090–1100 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    CAS  PubMed  Google Scholar 

  59. Wada, K., Itoga, K., Okano, T., Yonemura, S. & Sasaki, H. Hippo pathway regulation by cell morphology and stress fibers. Development 138, 3907–3914 (2011).

    CAS  PubMed  Google Scholar 

  60. Sansores-Garcia, L. et al. Modulating F-actin organization induces organ growth by affecting the Hippo pathway. EMBO J. 30, 2325–2335 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Fernandez, B. G. et al. Actin-Capping Protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila. Development 138, 2337–2346 (2011). References 58–61 described regulatory links between the Hippo pathway and the actin cytoskeleton and suggested that the pathway responds to mechanical stimuli.

    CAS  PubMed  Google Scholar 

  62. Butcher, D. T., Alliston, T. & Weaver, V. M. A tense situation: forcing tumour progression. Nature Rev. Cancer 9, 108–122 (2009).

    CAS  PubMed  Google Scholar 

  63. Simpson, C. D., Anyiwe, K. & Schimmer, A. D. Anoikis resistance and tumor metastasis. Cancer Lett. 272, 177–185 (2008).

    CAS  PubMed  Google Scholar 

  64. McClatchey, A. I. et al. Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev. 12, 1121–1133 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Chen, D. et al. LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker. Nature Med. 18, 1511–1517 (2012).

    CAS  PubMed  Google Scholar 

  66. Stauffer, J. K., Scarzello, A. J., Jiang, Q. & Wiltrout, R. H. Chronic inflammation, immune escape, and oncogenesis in the liver: a unique neighborhood for novel intersections. Hepatology 56, 1567–1574 (2012).

    CAS  PubMed  Google Scholar 

  67. Staley, B. K. & Irvine, K. D. Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation. Curr. Biol. 20, 1580–1587 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Shaw, R. L. et al. The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development 137, 4147–4158 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Karpowicz, P., Perez, J. & Perrimon, N. The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137, 4135–4145 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Grusche, F. A., Degoutin, J. L., Richardson, H. E. & Harvey, K. F. The Salvador/Warts/Hippo pathway controls regenerative tissue growth in Drosophila melanogaster. Dev. Biol. 350, 255–266 (2011).

    CAS  PubMed  Google Scholar 

  71. Sun, G. & Irvine, K. D. Regulation of Hippo signaling by Jun kinase signaling during compensatory cell proliferation and regeneration, and in neoplastic tumors. Dev. Biol. 350, 139–151 (2011).

    CAS  PubMed  Google Scholar 

  72. Cai, J. et al. The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 24, 2383–2388 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Hall, C. A. et al. Hippo pathway effector Yap is an ovarian cancer oncogene. Cancer Res. 70, 8517–8525 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Xu, M. Z. et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 115, 4576–4585 (2009).

    CAS  PubMed  Google Scholar 

  75. Wang, Y. et al. Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci. 101, 1279–1285 (2010).

    CAS  PubMed  Google Scholar 

  76. Evans, D. G. Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]. Genet. Med. 11, 599–610 (2009).

    PubMed  Google Scholar 

  77. Zender, L. et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253–1267 (2006). This paper, and reference 34, presented evidence that YAP1 is an oncogene and is amplified in human tumours.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. St John, M. A. et al. Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nature Genet. 21, 182–186 (1999).

    CAS  PubMed  Google Scholar 

  79. Zhou, D. et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16, 425–438 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lu, L. et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc. Natl Acad. Sci. USA 107, 1437–1442 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Song, H. et al. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc. Natl Acad. Sci. USA 107, 1431–1436 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Zhou, D. et al. Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proc. Natl Acad. Sci. USA 108, e1312–e1320 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Takahashi, Y. et al. Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin. Cancer Res. 11, 1380–1385 (2005).

    CAS  PubMed  Google Scholar 

  84. Jiang, Z. et al. Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci. Res. 56, 450–458 (2006).

    CAS  PubMed  Google Scholar 

  85. Seidel, C. et al. Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Mol. Carcinog. 46, 865–871 (2007).

    CAS  PubMed  Google Scholar 

  86. Tanas, M. R. et al. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci. Transl. Med. 3, 98ra82 (2011).

    PubMed  Google Scholar 

  87. Errani, C. et al. A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer 50, 644–653 (2011). References 86 and 87 discovered a chromosomal translocation causing the fusion of the genes encoding TAZ and CAMTA1 as the defining genetic lesion in epithelioid haemangioendothelioma.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Irvine, K. D. Integration of intercellular signaling through the Hippo pathway. Semin. Cell Dev. Biol. 23, 812–817 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. White, B. D., Chien, A. J. & Dawson, D. W. Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers. Gastroenterology 142, 219–232 (2012).

    CAS  PubMed  Google Scholar 

  90. Bellam, N. & Pasche, B. Tgf-β signaling alterations and colon cancer. Cancer Treat. Res. 155, 85–103 (2010).

    CAS  PubMed  Google Scholar 

  91. Cohen, D. J. Targeting the hedgehog pathway: role in cancer and clinical implications of its inhibition. Hematol. Oncol. Clin. North Am. 26, 565–588 (2012).

    PubMed  Google Scholar 

  92. Lobry, C., Oh, P. & Aifantis, I. Oncogenic and tumor suppressor functions of Notch in cancer: it's NOTCH what you think. J. Exp. Med. 208, 1931–1935 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Imajo, M., Miyatake, K., Iimura, A., Miyamoto, A. & Nishida, E. A molecular mechanism that links Hippo signalling to the inhibition of Wnt/β-catenin signalling. EMBO J. 31, 1109–1122 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Konsavage, W. M. et al. Wnt/β-catenin signaling regulates Yes-associated protein (YAP) gene expression in colorectal carcinoma cells. J. Biol. Chem. 287, 11730–11739 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Miller, E. et al. Identification of serum-derived sphingosine-1-phosphate as a small molecule regulator of YAP. Chem. Biol. 19, 955–962 (2012).

    CAS  PubMed  Google Scholar 

  96. Lin, S. et al. The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer. Gastroenterology 136, 1711–1720 (2009).

    CAS  PubMed  Google Scholar 

  97. Onken, M. D. et al. Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest. Ophthalmol. Vis. Sci. 49, 5230–5234 (2008).

    PubMed  Google Scholar 

  98. Prickett, T. D. et al. Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma. Nature Genet. 43, 1119–1126 (2011).

    CAS  PubMed  Google Scholar 

  99. Kan, Z. et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869–873 (2010).

    CAS  PubMed  Google Scholar 

  100. Van Raamsdonk, C. D. et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457, 599–602 (2009).

    CAS  PubMed  Google Scholar 

  101. Puca, R., Nardinocchi, L., Givol, D. & D'Orazi, G. Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells. Oncogene 29, 4378–4387 (2010).

    CAS  PubMed  Google Scholar 

  102. Poon, C. L., Zhang, X., Lin, J. I., Manning, S. A. & Harvey, K. F. Homeodomain-interacting protein kinase regulates hippo pathway-dependent tissue growth. Curr. Biol. 22, 1587–1594 (2012).

    CAS  PubMed  Google Scholar 

  103. Chen, J. & Verheyen, E. M. Homeodomain-interacting protein kinase regulates yorkie activity to promote tissue growth. Curr. Biol. 22, 1582–1586 (2012).

    CAS  PubMed  Google Scholar 

  104. Zhang, N. et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19, 27–38 (2010). This publication proved that YAP is a key driver of tumorigenesis and tissue overgrowth caused by loss of Nf2 in the murine liver.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Liu-Chittenden, Y. et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 26, 1300–1305 (2012). Porphyrin compounds were identified as potential antitumour agents on the basis of their ability to disrupt the interaction of the YAP oncoprotein with the TEAD1–4 transcription factors.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Michels, S. & Schmidt-Erfurth, U. Photodynamic therapy with verteporfin: a new treatment in ophthalmology. Semin. Ophthalmol. 16, 201–206 (2001).

    CAS  PubMed  Google Scholar 

  107. Agostinis, P. et al. Photodynamic therapy of cancer: an update. CA Cancer J. Clin. 61, 250–281 (2011).

    PubMed  PubMed Central  Google Scholar 

  108. Sjogren, B. Regulator of G protein signaling proteins as drug targets: current state and future possibilities. Adv. Pharmacol. 62, 315–347 (2011).

    CAS  PubMed  Google Scholar 

  109. Bao, Y. et al. A cell-based assay to screen stimulators of the Hippo pathway reveals the inhibitory effect of dobutamine on the YAP-dependent gene transcription. J. Biochem. 150, 199–208 (2011).

    CAS  PubMed  Google Scholar 

  110. Murph, M. & Mills, G. B. Targeting the lipids LPA and S1P and their signalling pathways to inhibit tumour progression. Expert Rev. Mol. Med. 9, 1–18 (2007).

    PubMed  Google Scholar 

  111. Fleming, J. K., Wojciak, J. M., Campbell, M. A. & Huxford, T. Biochemical and structural characterization of lysophosphatidic Acid binding by a humanized monoclonal antibody. J. Mol. Biol. 408, 462–476 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Wojciak, J. M. et al. The crystal structure of sphingosine-1-phosphate in complex with a Fab fragment reveals metal bridging of an antibody and its antigen. Proc. Natl Acad. Sci. USA 106, 17717–17722 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ponnusamy, S. et al. Communication between host organism and cancer cells is transduced by systemic sphingosine kinase 1/sphingosine 1-phosphate signalling to regulate tumour metastasis. EMBO Mol. Med. 4, 761–775 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Clair, T. et al. Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Cancer Res. 63, 5446–5453 (2003).

    CAS  PubMed  Google Scholar 

  115. Umezu-Goto, M. et al. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J. Cell Biol. 158, 227–233 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Stracke, M. L. et al. Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J. Biol. Chem. 267, 2524–2529 (1992).

    CAS  PubMed  Google Scholar 

  117. Tanaka, M. et al. Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. J. Biol. Chem. 281, 25822–25830 (2006).

    CAS  PubMed  Google Scholar 

  118. Xia, P. et al. An oncogenic role of sphingosine kinase. Curr. Biol. 10, 1527–1530 (2000).

    CAS  PubMed  Google Scholar 

  119. Van Brocklyn, J. R. et al. Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J. Neuropathol. Exp. Neurol. 64, 695–705 (2005).

    CAS  PubMed  Google Scholar 

  120. de Souza, P. L. et al. Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol), a novel isoflav-3-ene, in patients with advanced cancer. Cancer Chemother. Pharmacol. 58, 427–433 (2006).

    PubMed  Google Scholar 

  121. Kelly, M. G. et al. Phase II evaluation of phenoxodiol in combination with cisplatin or paclitaxel in women with platinum/taxane-refractory/resistant epithelial ovarian, fallopian tube, or primary peritoneal cancers. Int. J. Gynecol. Cancer 21, 633–639 (2011).

    PubMed  Google Scholar 

  122. Bertini, E., Oka, T., Sudol, M., Strano, S. & Blandino, G. YAP: at the crossroad between transformation and tumor suppression. Cell Cycle 8, 49–57 (2009).

    CAS  PubMed  Google Scholar 

  123. Louvi, A. & Artavanis-Tsakonas, S. Notch and disease: a growing field. Semin. Cell Dev. Biol. 23, 473–480 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Samanta, D. & Datta, P. K. Alterations in the Smad pathway in human cancers. Front. Biosci. 17, 1281–1293 (2012).

    CAS  Google Scholar 

  125. Barry, E. R. et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 493, 106–110 (2013).

    PubMed  Google Scholar 

  126. Altomare, D. A. et al. A mouse model recapitulating molecular features of human mesothelioma. Cancer Res. 65, 8090–8095 (2005).

    CAS  PubMed  Google Scholar 

  127. Giovannini, M. et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 14, 1617–1630 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kalamarides, M. et al. Nf2 gene inactivation in arachnoidal cells is rate-limiting for meningioma development in the mouse. Genes Dev. 16, 1060–1065 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Morris, Z. S. & McClatchey, A. I. Aberrant epithelial morphology and persistent epidermal growth factor receptor signaling in a mouse model of renal carcinoma. Proc. Natl Acad. Sci. USA 106, 9767–9772 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Benhamouche, S. et al. Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev. 24, 1718–1730 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Kim, T. S. et al. Mammalian sterile 20-like kinase 1 (Mst1) suppresses lymphoma development by promoting faithful chromosome segregation. Cancer Res. 72, 5386–5395 (2012).

    CAS  PubMed  Google Scholar 

  132. Lee, K. P. et al. The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis. Proc. Natl Acad. Sci. USA 107, 8248–8253 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Nishio, M. et al. Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice. J. Clin. Invest. 122, 4505–4518 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Varelas, X. et al. The Hippo pathway regulates Wnt/β-catenin signaling. Dev. Cell 18, 579–591 (2010). This paper, together with reference 30, discovered mechanisms of crosstalk between the Hippo and WNT pathways.

    CAS  PubMed  Google Scholar 

  135. Alarcon, C. et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-β pathways. Cell 139, 757–769 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Fernandez, L. A. et al. YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev. 23, 2729–2741 (2009).

    Google Scholar 

  137. Tumaneng, K. et al. YAP mediates crosstalk between the Hippo and PI(3)K-TOR pathways by suppressing PTEN via miR-29. Nature Cell Biol. 14, 1322–1329 (2012).

    CAS  PubMed  Google Scholar 

  138. Polesello, C. & Tapon, N. Salvador-warts-hippo signaling promotes Drosophila posterior follicle cell maturation downstream of notch. Curr. Biol. 17, 1864–1870 (2007).

    CAS  PubMed  Google Scholar 

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Acknowledgements

K.F.H. is a Sylvia and Charles Viertel Senior Medical Research Fellow. X.Z. is a Cure Cancer Australia and National Breast Cancer Foundation fellow. D.M.T is an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellow.

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Correspondence to Kieran F. Harvey or David M. Thomas.

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Supplementary information

Supplementary information S1 (table)

Detailed somatic mutations in Hippo pathway genes in human cancer (PDF 361 kb)

Glossary

14-3-3 binding sites

Peptide sequences that bind to 14-3-3 proteins when phosphorylated. 14-3-3 proteins often function as adaptor proteins or subcellular localizers of their protein substrates.

Anoikis

Apoptosis resulting from inappropriate attachment of cells to a substrate.

Pluripotency

The capability of cells to give rise to multiple lineages.

Non-canonical WNT signalling

WNT signalling that is independent of β-catenin.

Adherens junctions

Intercellular junctions important for epithelial cell–cell adhesion.

Tight junctions

Intercellular junctions that form at the apical regions of epithelial cells.

Driver mutations

Mutations that are actively involved in tumour formation.

Passenger mutations

Mutations that are present in cancers but that do not promote tumour formation.

Pathognomonic

Distinctive for a particular disease.

Epithelioid haemangioendothelioma

A rare vascular tumour characterized by TAZ–CAMTA1 gene fusions.

Photocoagulation therapy

Light-based method used especially for treating retinal tears.

Photodynamic therapy

Activation of photosensitive compounds by light.

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Harvey, K., Zhang, X. & Thomas, D. The Hippo pathway and human cancer. Nat Rev Cancer 13, 246–257 (2013). https://doi.org/10.1038/nrc3458

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