@article{ea0f7f713d1141b2ab23ae5b0ac52ce3,
title = "Gα13 loss in Kras/Tp53 mouse model of pancreatic tumorigenesis promotes tumors susceptible to rapamycin",
abstract = "Gα13 transduces signals from G-protein-coupled receptors. While Gα13 functions as a tumor suppressor in lymphomas, it is not known whether Gα13 is pro-tumorigenic or tumor suppressive in genetically engineered mouse (GEM) models of epithelial cancers. Here, we show that loss of Gα13 in the Kras/Tp53 (KPC) GEM model promotes well-differentiated tumors and reduces survival. Mechanistically, tumors developing in KPC mice with Gα13 loss exhibit increased E-cadherin expression and mTOR signaling. Importantly, human pancreatic ductal adenocarcinoma (PDAC) tumors with low Gα13 expression also exhibit increased E-cadherin expression and mTOR signaling. Treatment with the mTOR inhibitor rapamycin decreases the growth of syngeneic KPC tumors with Gα13 loss by promoting cell death. This work establishes a tumor-suppressive role of Gα13 in pancreatic tumorigenesis in the KPC GEM model and suggests targeting mTOR in human PDAC tumors with Gα13 loss.",
keywords = "E-cadherin, Gα13, KC mouse model, KPC mouse model, human PDAC tumors, mTOR, rapamycin",
author = "Shields, {Mario A.} and Christina Spaulding and Metropulos, {Anastasia E.} and Khalafalla, {Mahmoud G.} and Pham, {Thao N.D.} and Munshi, {Hidayatullah G.}",
note = "Funding Information: We thank Dr. Stefan Offermanns (Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany) who kindly provided the Gna13 flox/flox mice. This work was supported by grants R01CA217907 (to H.G.M.) and R21CA255291 (to H.G.M.) from the NCI, United States; a merit award I01BX002922 (to H.G.M.) from the Department of Veterans Affairs, United States ; an H Foundation award and APA/APA Foundation 2020 Young Investigator in Pancreatology grant (to M.A.S.); a Mander Foundation award (to H.G.M.); a Harold E. Eisenberg Foundation award (to T.N.D.P.) from the Robert H. Lurie Comprehensive Cancer Center ; and an NIH/NCI training grant T32 CA070085 (to T.N.D.P). This work was supported by the Northwestern University Pathology Core Facility and the Northwestern University Center for Advanced Microscopy , both generously supported by NCI CCSG P30 CA060553 , awarded to the Robert H. Lurie Comprehensive Cancer Center. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = mar,
day = "1",
doi = "10.1016/j.celrep.2022.110441",
language = "English (US)",
volume = "38",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "9",
}
