Data from Oncogenic GNAS Uses PKA-Dependent and Independent Mechanisms to Induce Cell Proliferation in Human Pancreatic Ductal and Acinar Organoids

Abstract

Ductal and acinar pancreatic organoids are promising models for the study of pancreatic diseases. Genome sequencing studies have revealed that mutations in a G-protein (GNAS^R201C) are exclusively observed in intraductal papillary mucinous neoplasms (IPMN). The biological mechanisms by which GNAS^R201C affects the ductal and acinar exocrine pancreas are unclear. Here, we use human stem-cell-derived pancreatic ductal and acinar organoids and demonstrate that GNAS^R201C was more effective in inducing proliferation in ductal organoids compared with acinar organoids. Surprisingly, GNAS^R201C-induced cell proliferation was protein kinase A (PKA)-independent in ductal organoids and an immortalized ductal epithelial cell line. Co-expression of oncogenic KRASG12V and GNAS^R201C retained PKA-independence in ductal organoids to stimulate cell proliferation. Thus, we identify cell lineage-specific roles for PKA signaling in GNAS^R201C-driven cell proliferation in precancerous lesions and report the development of a human pancreatic ductal organoid model system to investigate mechanisms regulating GNAS^R201C-induced IPMNs.

Implications:

The study identifies an opportunity to discover a PKA-independent pathway downstream of oncogene GNAS for managing IPMN lesions and their progression to PDAC.