We have recently identified the Mst1/2 ser/thr kinases as important hepatocellular carcinoma (HCC) tumor suppressors. Mst1/2 are the orthologs of the Drosophila tumor suppressor Hippo, which promotes apoptosis and inhibits cell proliferation during development. Hippo action is mediated by a set of critical substrates which are conserved in humans, and which in turn suppress the transcriptional coactivator, Yorkie, whose human ortholog, Yap, is an established oncogene and regulator of organ size. By generating Mst1/2 KO mice we found that Mst1 and Mst2 are required to maintain quiescence of liver cells and that their liver-specific ablation results in Yap activation, liver overgrowth, resistance to apoptosis, and the rapid development of HCC. Significantly, we have determined that ~30% of human HCCs have deregulation of the Mst1/2-Yap signaling axis. These results establish Mst1/2 as important tumor suppressors relevant to the pathogenesis of HCC in humans and point to Yap as one critical downstream target. Although Mst1/Mst2 lie at the center of an important growth control network, much about the physiologic regulation and functions of Mst1/2 and their role as tumor suppressors remains to be determined. We find that the upstream regulation and outputs of Mst1 and Mst2 in mammalian cells differ markedly from those predicted by the Drosophila Hippo pathway and by in vitro overexpression studies. In murine naive T cells, e.g., Mst1/2 negatively regulate proliferation independently of Yap. Moreover Mst1/2 are constitutive partners of the Rassf family of tumor suppressor polypeptides, some of which (e.g., Nore1/Rassf5) are regulated by Ras-like GTPases. Which of these multiple upstream elements control Mst1/Mst2 in liver is an open question. This proposal describes a systematic approach to define in molecular terms the upstream regulatory inputs and critical outputs of Mst1/2 that determine the capacity of Mst1/2 to regulate liver growth and exert tumor suppression in vivo. The regulation of Yap and its contribution to carcinogenesis will be investigated in detail. We have also identified Yap- independent responses to Mst1/2 deficiency, whose mechanism of activation and contribution to the malignant transformation of hepatocytes will be determined. Finally we will characterize the human HCCs that exhibit deregulation of the Mst1/Mst2 pathway, and determine how such deregulation influences the histopathologic and clinical features of human HCC. These studies are likely to reveal new strategies for the therapy of HCC and as well as of other human cancers that have defective regulation of the Mst1/2 kinases.

Public Health Relevance

MST1 and MST2 are two very similar protein kinases that are central parts of a network of tumor suppressors and oncogenes. Deletion of both together in mouse liver produces liver cancer. We want to find out how they are regulated, the identity of their key targets in suppressing tumor development, how their removal enables liver cancer to develop and their role in human liver cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136567-04
Application #
8450270
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Watson, Joanna M
Project Start
2010-07-06
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$574,756
Indirect Cost
$230,207
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Moeini, Agrin; Sia, Daniela; Bardeesy, Nabeel et al. (2016) Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma. Clin Cancer Res 22:291-300
Fitamant, Julien; Kottakis, Filippos; Benhamouche, Samira et al. (2015) YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression. Cell Rep :
Geng, Jing; Sun, Xiufeng; Wang, Ping et al. (2015) Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nat Immunol 16:1142-52
Kelley, Robin K; Bardeesy, Nabeel (2015) Biliary Tract Cancers: Finding Better Ways to Lump and Split. J Clin Oncol 33:2588-90
Saha, Supriya K; Parachoniak, Christine A; Ghanta, Krishna S et al. (2014) Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature 513:110-4
Crose, Lisa E S; Galindo, Kathleen A; Kephart, Julie Grondin et al. (2014) Alveolar rhabdomyosarcoma-associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression. J Clin Invest 124:285-96
Borger, Darrell R; Goyal, Lipika; Yau, Thomas et al. (2014) Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma. Clin Cancer Res 20:1884-90
Saha, Supriya K; Parachoniak, Christine A; Bardeesy, Nabeel (2014) IDH mutations in liver cell plasticity and biliary cancer. Cell Cycle 13:3176-82
Regué, Laura; Mou, Fan; Avruch, Joseph (2013) G protein-coupled receptors engage the mammalian Hippo pathway through F-actin: F-Actin, assembled in response to Galpha12/13 induced RhoA-GTP, promotes dephosphorylation and activation of the YAP oncogene. Bioessays 35:430-5
Gao, Tao; Zhou, Dawang; Yang, Chenghua et al. (2013) Hippo signaling regulates differentiation and maintenance in the exocrine pancreas. Gastroenterology 144:1543-53, 1553.e1

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