de Winter, T. J. J. | bioRxiv Science

bioRxiv2021

Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics

Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that a [~]50% reduction in pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice could be achieved with reduced insulin production. However, only female mice remained normoglycemic and only the gene dosage of rodent-specific Ins1 alleles was tested in our previous model. Moreover, we did not delve into the molecular and cellular mechanisms associated with modulating hyperinsulinemia. Here, we studied PanIN lesion development in both male and female Ptf1aCreER;KrasLSL-G12D mice lacking the rodent specific Ins1 gene, and possessing one or two alleles of the wild-type Ins2 gene to modulate insulin production. High-fat diet induced hyperinsulinemia was transiently and modestly reduced, without affecting glucose tolerance, in male and female mice with only one allele of Ins2. Genetic reduction of insulin production resulted in mice with a tendency for less PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia affected multiple cell types in the pancreas, with the most statistically significant effects on local immune cell populations, which were highly represented in our analysis. Specifically, hyperinsulinemia modulated pathways associated with protein translation, MAPK-ERK signaling, and PI3K-AKT signaling, which were changed in epithelial cells and subsets of immune cells. These data suggest a role for the immune microenvironment in hyperinsulinemia-driven PanIN development. Together with our previous work, we propose that mild suppression of insulin levels may be useful in preventing pancreatic cancer by acting on multiple cell types.

cancer biology↗

bioRxiv2019

Endogenous insulin contributes to pancreatic cancer development

Obesity and early-stage type 2 diabetes (T2D) increase the risk for many cancers, including pancreatic ductal adenocarcinoma (PDAC). The mechanisms linking obesity and T2D to cancer have not been established, preventing targeted interventions. Arguments have been made that hyperinsulinemia, hyperglycemia, or inflammation could drive cancer initiation and/or progression1. Hyperinsulinemia is a cardinal feature of obesity and T2D, and is independently associated with PDAC incidence and mortality2-4, even in non-obese people5. Despite ample human epidemiological evidence linking hyperinsulinemia to PDAC, there is no direct in vivo evidence of a causal role for endogenous insulin in cancer in any system. Using mice with reduced insulin gene dosage6, 7, we show here that a modest reduction in endogenous insulin production leads to a ~50% reduction in pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in high fat diet-fed mice expressing the KrasG12D oncogene8. The significant reduction in PanIN lesions occurred in the absence of changes in fasting glucose. Reduced insulin also led to a ~50% reduction in pancreatic fibrosis, suggesting that endogenous insulin drives PanIN development, in part, via its pro-fibrotic effects on the stroma surrounding acinar cells and PanIN. Collectively, our data indicate that endogenous insulin hypersecretion contributes causally to pancreatic cancer development. This suggests a modest reduction in fasting insulin via lifestyle interventions or therapeutics may be useful in cancer prevention.

cancer biology↗