Gα13 loss in Kras/Tp53 mouse model of pancreatic tumorigenesis promotes tumors susceptible to rapamycin.
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.
Pubmed ID: 35235808 RIS Download
Research resources used in this publication
- Aperio ImageScope (RRID:SCR_020993) (software resource)
- Fiji (RRID:SCR_002285) (software resource)
- Northwestern University Feinberg School of Medicine Center for Advanced Microscopy Nikon Imaging Center Core Facility (RRID:SCR_020996) (service resource)
- GraphPad Prism (RRID:SCR_002798) (software resource)
- B6N.Cg-Krastm4Tyj/CjDswJ (RRID:IMSR_JAX:019104) (organism)
- 129S-Trp53tm2Tyj/J (RRID:IMSR_JAX:008652) (organism)
- B6.FVB-Tg(Pdx1-cre)6Tuv/J (RRID:IMSR_JAX:014647) (organism)
- Anti-Glyceraldehyde-3-Phosphate Dehydrogenase Antibody, clone 6C5 (RRID:AB_2107445) (antibody)
- HSP 90alpha/beta (H-114) (RRID:AB_2121235) (antibody)
- Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb (RRID:AB_916156) (antibody)
- Recombinant Anti-mTOR (phospho S2448) antibody [EPR426(2)] (RRID:AB_10888105) (antibody)
- mTOR (7C10) Rabbit mAb (RRID:AB_2105622) (antibody)
Additional research tools detected in this publication
Antibodies used in this publication
- HSP 90alpha/beta (H-114) (RRID:AB_2121235)
- Anti-Glyceraldehyde-3-Phosphate Dehydrogenase Antibody, clone 6C5 (RRID:AB_2107445)
- Recombinant Anti-mTOR (phospho S2448) antibody [EPR426(2)] (RRID:AB_10888105)
- mTOR (7C10) Rabbit mAb (RRID:AB_2105622)
- Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb (RRID:AB_916156)
- Goat anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ Plus 488 (RRID:AB_2633280)
- Goat anti-Rat IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 594 (RRID:AB_10561522)
- Anti-Mouse IgG (whole molecule)-Peroxidase antibody produced in goat (RRID:AB_258167)
- Anti-Rabbit IgG (whole molecule), F(ab)2 fragment-Peroxidase antibody produced in goat (RRID:AB_258307)
- Rabbit Anti-PDK1, phospho (Ser241) Monoclonal Antibody, Unconjugated, Clone C49H2 (RRID:AB_2161134)
- PDK1 (D37A7) Rabbit mAb (RRID:AB_10839264)
- Rabbit Anti-S6 Ribosomal Protein Monoclonal Antibody, Unconjugated, Clone 5G10 (RRID:AB_331355)
- Cleaved Caspase-3 (Asp175) (5A1E) Rabbit mAb (RRID:AB_2070042)
- Ki-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (RRID:AB_2620142)
- Cytokeratin 19 antibody [EP1580Y] (RRID:AB_2281020)
- Keratin, type I; cytokeratin 19 antibody - Kemler, R.; MPI fuer Immunobiologie (RRID:AB_2133570)
- E-Cadherin (24E10) Rabbit mAb (RRID:AB_2291471)
Associated grants
- Agency: NCI NIH HHS, United States
Id: R21 CA255291 - Agency: NCI NIH HHS, United States
Id: P30 CA060553 - Agency: BLRD VA, United States
Id: I01 BX002922 - Agency: NCI NIH HHS, United States
Id: T32 CA070085 - Agency: NCI NIH HHS, United States
Id: R01 CA217907
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This is a list of tools and resources that we have found mentioned in this publication.
Jackson Laboratory (tool)
RRID:SCR_004633
An independent, nonprofit organization focused on mammalian genetics research to advance human health. Their mission is to discover the genetic basis for preventing, treating, and curing human disease, and to enable research for the global biomedical community. Jackson Laboratory breeds and manages colonies of mice as resources for other research institutions and laboratories, along with providing software and techniques. Jackson Lab also conducts genetic research and provides educational material for various educational levels.
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RRID:SCR_020996
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RRID:SCR_002798
Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
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RRID:IMSR_JAX:019104
Mus musculus with name B6N.Cg-Krastm4Tyj/CjDswJ from IMSR.
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RRID:AB_2121235
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