Abstract PO-060: Gna13 delays disease progression in mouse models of pancreatitis and pancreatic cancer

We previously reported that Gα13 (Gna13), a member of the G12 heterotrimeric G proteins, is upregulated in pancreatic cancer patients and contributes to invasion in cancer cells in vitro. While other reports have demonstrated a tumor promoting function of Gα13 in solid tumors, Gα13 functions as a tumor suppressor in mouse models of B cell lymphoma. In this study, we evaluated the role of Gα13 in mouse models of pancreatitis and pancreatic cancer. To examine the role of Gα13 in pancreatic cancer development and progression, we crossed mice with a floxed allele of Gna13 to mice expressing oncogenic KrasG12D (KrasG12D;Pdx1-Cre). In parallel, we measured transplanted tumors established from pancreatic cell lines, where Gna13 is silenced or deleted. Further, we determined how loss of Gα13 influences cerulein-induced pancreatitis and inflammation-driven tumor progression in mice. Tumors derived from Gα13-deficient cells grew significantly slower than control cells when transplanted in either the orthotopic or subcutaneous site. However, cancer development and overall survival were unaffected in mice with heterozygous loss of Gα13, when compared to mice with intact expression of Gα13. Interestingly, in an aggressive cancer model (KrasG12D;P53R172H;Pdx1-Cre) loss of Gα13 led to faster tumor development and decreased overall survival. Furthermore, we found that Gα13 loss leads to enhanced inflammation and more progressive acinar-ductal metaplasia in pancreatitis. Overall, our results demonstrate a context-dependent role of Gα13 in the pancreas. Similar to previous reports, we show that inhibiting Gα13 in cancer cell lines limits tumor growth in vivo. However, in a genetic mouse model, loss of Gα13 promotes pancreatitis-induced inflammation and promotes tumor development and progression. Citation Format: Mario A. Shields, Christina Spaulding, Mahmoud G. Khalafalla, Thao D.N. Pham, Hidayatullah G. Munshi. Gna13 delays disease progression in mouse models of pancreatitis and pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-060.