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Insulin receptor signaling in pancreatic acinar cells contributes to KrasG12D-driven cancer initiation in the context of diet-induced obesity

ABSTRACT: Phosphoproteomic analysis to elucidate whether high-fat diet induced hyperinsulinemia contributes to pancreatic cancer directly through insulin receptor (INSR) signaling in KrasG12D-expressing pancreatic acinar cells.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Pancreas

DISEASE(S): Pancreatic Cancer

SUBMITTER: Vincent Richard

LAB HEAD: Christoph H Borchers

PROVIDER: PXD033845 | Pride | 2023-10-19

REPOSITORIES: Pride

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			Action	DRS
	QE007454_VR_SCPC_046_03_phospho_10_KO_G_2063.raw	Raw
	QE007455_VR_SCPC_046_03_phospho_17_KO_G_1905.raw	Raw
	QE007456_VR_SCPC_046_03_phospho_14_KO_G12D_2070.raw	Raw
	QE007457_VR_SCPC_046_03_phospho_19_WT_G_1790.raw	Raw
	QE007458_VR_SCPC_046_03_phospho_9_WT_G12D_1860.raw	Raw

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Project description:The rising incidence of pancreatic cancer is largely driven by the skyrocketing prevalence of obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of both conditions, and is independently associated with increased cancer incidence and mortality. Our previous studies demonstrated that genetically reducing insulin production suppressed formation of pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice with mutant Kras. However, we found that hyperinsulinemia affected many cell types in the pancreatic microenvironment. Thus, it remained unclear whether hyperinsulinemia exerted its effects directly on the cells that give rise to PanINs or indirectly on the tumor microenvironment, and molecular mechanisms involved were unknown. Here, we tested whether insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are necessary for the effects of hyperinsulinemia on obesity-associated pancreatic cancer development. Loss of Insr in KrasG12D-expressing acinar cells did not prevent hyperinsulinemia or weight gain associated with high fat diet (HFD) consumption in mice. However, solely reducing Insr in KrasG12D-expressing acinar cells significantly reduced formation of PanIN and tumors, in a gene dose-dependent manner. Mechanistically, proteomic analyses showed that hyperinsulinemia acts through Insr to drive the excess production of digestive enzymes in acinar cells by modulating the activity of the spliceosome, ribosome, and secretory machinery. This resulted in increased inflammation, which was abrogated by acinar-specific Insr knockout. We confirmed that insulin increased the conversion of wild-type acinar cells into acinar-to-ductal metaplasia (ADM) in a trypsin-dependent manner. Collectively, these data demonstrate that hyperinsulinemia acting via acinar cells insulin receptors promotes inflammatory conditions that cooperate with Kras signaling to increase the risk of developing pancreatic cancer, mechanistically linking obesity and pancreatic cancer.

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Insulin receptor signaling in pancreatic acinar cells contributes to KrasG12D-driven cancer initiation in the context of diet-induced obesity

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