Abstract PO-056: Insulin receptor signaling in pancreatic acinar cells contributes to pancreatic cancer development

Abstract

Abstract Hyperinsulinemia is a cardinal feature shared by both obesity and type 2 diabetes, and is independently associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). We previously showed a ~50% reduction in pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice with genetically reduced insulin production. Our single-cell transcriptomic data suggested that many pancreatic cell types could mediate the effects of local hyperinsulinemia on PanIN development. In pancreatic acinar cells from mice with reduced insulin, we found alterations in the PI3K/AKT/mTOR and MAPK/ERK pathways known to be involved in tumorigenesis. Here, we examined whether hyperinsulinemia contributes to PDAC development directly through insulin receptor signaling in KrasG12D expressing pancreatic acinar cells. To test this hypothesis, we generated Ptf1aCreER;LSL-KrasG12D;nTnG mice with an Insrwt/wt (PK-Insrwt/wt), Insrwt/fl (PK-Insrwt/fl), or Insrfl/fl (PK-Insrfl/fl) genotype to reduce insulin receptor signaling by 0%, 50%, or 100% in acinar cells, in both males and females. We fed the mice with high-fat diet (HFD) to induce systemic hyperinsulinemia and tracked body weight, fasting glucose and fasting insulin levels routinely. We euthanized the mice when they were 10 months old and performed blinded histopathological analysis and immunohistochemistry staining of the pancreatic sections to assess the PanIN formation. Loss of insulin receptors from acinar cells did not significantly influence body weight, fasting glucose or fasting insulin levels. Alcian blue staining of mucins contained within low-grade PanINs showed that there was a significant reduction in these pre-cancerous lesions in PK-Insrwt/fl and PK-Insrfl/fl female mice compared to PK-Insrwt/wt mice and the difference was Insr gene dosage-dependent. By performing immunohistochemical staining of CK19, marking duct and duct-like cells, we found there was a significant reduction of CK19+ area in PK-Insrwt/fl and PK-Insrfl/fl mice compared to PK-Insrwt/wt mice, and the reduction was Insr gene dosage-dependent. Finally, we found a significant increase in retention of normal acinar cells in PK-Insrfl/fl mice compared to PK-Insrwt/wt mice, which indicates the mice losing Insr had more wild-type like pancreas. Collectively, these data strongly suggest that insulin receptor signaling in acinar cells is important for the metaplasia formation, but do not exclude a role of Insr on other local or distant cell types. Prophylactic approaches targeting insulin receptor signaling pathways, or hyperinsulinemia itself, may be beneficial in preventing pancreatic cancer. Citation Format: Anni M. Y. Zhang, Jenny C. C. Yang, Twan J. J. de Winter, David F. Schaeffer, Janel L. Kopp, James D. Johnson. Insulin receptor signaling in pancreatic acinar cells contributes to pancreatic cancer development [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-056.