Grant: CIHR-ICR / Cancer Research Society Partnership - Res. Gr. Cancer Prev.

Intraductal papillary mucinous neoplasia (IPMN) and pancreatic intraepithelial neoplasia (PanIN) are precursors to pancreatic ductal adenocarcinoma (PDAC). IPMN primarily arise from pancreatic ductal cells, while PanIN largely arise from acinar cells. IPMN are large and detected in routine, medical imaging. Because of this, they are also often detected in high-risk individuals undergoing routine monitoring. This means that there is a population of patients that would significantly benefit from the identification of interventions that would limit initiation and/or progression. Long-standing diabetes, insulin treatment, and obesity have been associated with risk of PDAC and IPMN, as well as risk of IPMN progression. However, the underlying mechanisms driving these associations are unknown. Hyperinsulinemia, is common to both metabolic diseases and may be the factor underlying this increased cancer risk. Insulin/insulin receptor signaling affects both the RAS/MAPK/ERK and PI3K/PTEN/AKT signaling pathways, but the output of these signals is cell type dependent. Oncogenic mutations in KRAS are present in both IPMN and PanIN, while mutations in the PI3K signaling pathway (PTEN, PIK3CA) are more common in IPMN. We’ve previously shown that insulin/insulin receptor signaling in acinar cells increases production of digestive enzymes leading to a local inflammatory, field-effect ultimately resulting in transformation of KRASG12Dexpressing acinar cells into PanIN. Because ductal cells have a different physiological function, we hypothesize obesity is associated with the risk of developing IPMN because of the direct effects of insulin on the survival of ductal cells. Indeed, our previous studies on primary human ductal cells indicates insulin regulates survival, not proliferation. Alternatively, others have suggested that obesityassociated systemic inflammation suppresses apical extrusion when oncogenic Ras is expressed in ductal cells. However, neither of these studies tested the long-term effects of obesity or hyperinsulinemia on ductal cell transformation into precancerous lesions in physiologically relevant in vivo models. In this first two-year grant, we will pursue the following aims: Aim 1. Determine whether high fat diet promotes IPMN development. In this aim, we will test whether high fat diet induced hyperinsulinemia can increase the frequency of IPMN initiation or the progression to PDAC in a stochastic mouse model of IPMN. To do this, we will use our ductal-cell specific Sox9CreER;Ptenf/f mice, which recapitulates many aspects of human IPMN. We will feed these mice high fat diet for 1 year and then quantify the number and type of precancerous lesions formed from Pten null ductal cells. We expect these foundational studies will provide experimental evidence that obesity can increase the risk of IPMN initiation. In future studies, we will utilize our expertise in modulating the levels of insulin and insulin receptor signaling to specifically test the hypotheses that hyperinsulinemia directly promotes cancer initiation from ductal cells.