Gα13 loss in Kras/Tp53 mouse model of pancreatic tumorigenesis promotes tumors susceptible to rapamycin

Mario A. Shields; Christina Spaulding; Anastasia E. Metropulos; Mahmoud G. Khalafalla; Thao N.D. Pham; Hidayatullah G. Munshi

doi:10.1016/j.celrep.2022.110441

Gα13 loss in Kras/Tp53 mouse model of pancreatic tumorigenesis promotes tumors susceptible to rapamycin

Mario A. Shields^*, Christina Spaulding, Anastasia E. Metropulos, Mahmoud G. Khalafalla, Thao N.D. Pham, Hidayatullah G. Munshi^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Article number	110441
Journal	Cell reports
Volume	38
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2022.110441
State	Published - Mar 1 2022

Funding

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.

Keywords

E-cadherin
Gα13
KC mouse model
KPC mouse model
human PDAC tumors
mTOR
rapamycin

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2022.110441

Cite this

@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 = "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",

}

TY - JOUR

T1 - Gα13 loss in Kras/Tp53 mouse model of pancreatic tumorigenesis promotes tumors susceptible to rapamycin

AU - Shields, Mario A.

AU - Spaulding, Christina

AU - Metropulos, Anastasia E.

AU - Khalafalla, Mahmoud G.

AU - Pham, Thao N.D.

AU - Munshi, Hidayatullah G.

PY - 2022/3/1

Y1 - 2022/3/1

N2 - 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.

AB - 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.

KW - E-cadherin

KW - Gα13

KW - KC mouse model

KW - KPC mouse model

KW - human PDAC tumors

KW - mTOR

KW - rapamycin

UR - http://www.scopus.com/inward/record.url?scp=85125231297&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85125231297&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2022.110441

DO - 10.1016/j.celrep.2022.110441

M3 - Article

C2 - 35235808

AN - SCOPUS:85125231297

SN - 2211-1247

VL - 38

JO - Cell reports

JF - Cell reports

IS - 9

M1 - 110441

ER -

Gα13 loss in Kras/Tp53 mouse model of pancreatic tumorigenesis promotes tumors susceptible to rapamycin

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this