Abstract B055: Hyperinsulinemia acts via acinar cell insulin receptors to drive obesity-associated pancreatic cancer initiation

Abstract

Abstract The rising incidence of pancreatic cancer is largely driven by increased prevalence of obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of obesity and T2D, and is associated with increased cancer incidence and mortality. Whether insulin alone plays a causal role in increasing cancer risk by directly affecting the tumor cell of origin remains unclear. Our previous studies demonstrated that genetically reducing production of insulin suppressed formation of pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice with mutant Kras. However, consistent with a role for insulin in modulating the immune system, we saw changes in fibrosis, as well as changes in the transcriptomes of immune cells in the pancreas in mice with reduced insulin. Thus, it remained unclear whether hyperinsulinemia exerted its effects directly on the cells that give rise to PanINs or indirectly on the tumor microenvironment. Here, we tested whether insulin receptor (Insr) in KrasG12D-expressing pancreatic acinar cells was necessary for the effects of diet-induced hyperinsulinemia on pancreatic cancer development. Loss of Insr in KrasG12D-expressing acinar cells did not halt the development of hyperinsulinemia or weight gain associated with high fat diet consumption in mice. However, solely reducing Insr expression in KrasG12D-expressing acinar cells significantly reduced formation of PanIN and tumors. Mechanistically, proteomic analyses suggested that insulin and Insr coordinately regulate the production of digestive enzymes, the main function of acinar cells, by modulating the activity of the spliceosome, ribosome, and secretory machinery. Consistent with this adding insulin to TGF-alpha treated wild-type acini ex vivo increased their conversion into ductal structures and this was blocked by treatment with trypsin inhibitor. Additionally, loss of Insr also reduced the formation of duct-like structures in acinar explants after TGF-alpha stimulation and made them insensitive to insulin. Collectively, these data demonstrated that insulin action on the insulin receptor in acinar cells promotes conditions that cooperate with Kras signaling to increase the risk of developing pancreatic cancer especially in the context of hyperinsulinemia and obesity. Citation Format: Anni M.Y. Zhang, Yi Han Xia, Jeffrey S.H. Lin, Ken H. Chu, Wei Chuan K. Wang, Titine J.J. Ruiter, Jenny C.C. Yang, Nan Chen, Justin Chhuor, Shilpa Patil, Haoning H. Cen, Elizabeth J. Rideout, Vincent R. Richard, David F. Schaeffer, Rene P. Zahedi, Christoph H. Borchers, James D. Johnson, Janel L. Kopp. Hyperinsulinemia acts via acinar cell insulin receptors to drive obesity-associated pancreatic cancer initiation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B055.