Oncogenic GNAS uses PKA-dependent and independent mechanisms to induce cell proliferation in human pancreatic ductal and acinar organoids.

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 (GNASR201C) are exclusively observed in intraductal papillary mucinous neoplasms (IPMNs). The biological mechanisms by which GNASR201C affects the ductal and acinar exocrine pancreas are unclear. Here, we use human stem-cell-derived pancreatic ductal and acinar organoids and demonstrate that GNASR201C was more effective in inducing proliferation in ductal organoids compared to acinar organoids. Surprisingly, GNASR201C-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 GNASR201C retained PKA-independence in ductal organoids to stimulate cell proliferation. Thus, we identify cell lineage-specific roles for PKA signaling in GNASR201C-driven cell proliferation in pre-cancerous lesions and report the development of a human pancreatic ductal organoid model system to investigate mechanisms regulating GNASR201C-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.