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Oncogenic GNAS-induced proliferation is dependent on MAPK signaling in pancreatic ductal organoids
Thesis

Oncogenic GNAS-induced proliferation is dependent on MAPK signaling in pancreatic ductal organoids

Vidula Shantilal Jadhav
Master of Science (M.S.), Drexel University
Jul 2026
DOI:
https://doi.org/10.17918/00011520
pdf
Jadhav_Vidula_20268.84 MB
PDF Embargoed Access, Embargo ends: 31 Aug 2028

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is often diagnosed after local invasion or metastasis has occurred. Among pancreatic precursor lesions, intraductal papillary mucinous neoplasms (IPMNs) are clinically important because they can be detected before progression to invasive disease. IPMNs frequently harbor activating mutations in KRAS and are reported in ~40-80% of IPMNs. In addition to KRAS, GNAS mutations are found in ~40-75% of IPMNs, and these are exclusive to IPMNs. Oncogenic GNAS encodes the stimulatory G-protein alpha subunit G[alpha]s, particularly at the R201 hotspot. Constitutive activation of GNAS stimulates cyclic AMP-dependent protein kinase A (PKA) signaling and other downstream pathways to regulate many cell biological processes. Previous studies using human stem cell-derived ductal and acinar organoids showed that oncogenic GNAS^[R201C] induces ductal-specific proliferation independent of PKA signaling. However, the mechanism by which oncogenic GNAS drives PKA-independent proliferation remains unknown. Given that epidermal growth factor (EGF)-induced MAPK (Mitogen-Activated Protein Kinase) signaling is essential for pancreatic ductal cell proliferation, we examined whether oncogenic GNAS-expressing ductal organoids can alter proliferation of ductal cells in the absence of exogenous EGF. Phase-contrast imaging, EdU (5-ethynly-2'-deoxyuridine) based proliferation assays, serial passaging collectively indicate that oncogenic GNAS-expressing ductal organoids proliferate in the absence of exogenous EGF. In addition, the proliferation of oncogenic GNAS^[R201C]-expressing ductal organoids under EGF-deprived conditions appears to be PKA-independent. Interestingly we found that pharmacological inhibition of MAPK signaling, using MEK inhibitors - Trametinib and Selumitinib is sufficient to block oncogenic GNAS-induced ductal cell proliferation, suggesting that GNAS-induced ductal proliferation is dependent on MAPK signaling. In the future, it will be important to understand how oncogenic GNAS influences MAPK signaling and whether specific MAPK effector proteins are necessary for oncogenic GNAS-induced ductal cell proliferation. In addition, it will also be interesting to investigate whether oncogenic GNAS-induced proliferation is dependent on MAPK signaling in other cell types such as pancreatic acini organoids. Together with our current preliminary results, this study provides crucial insights in uncovering signaling pathways necessary mechanisms that drive oncogenic GNAS dependent proliferation of pancreatic ductal cells, and consequently in designing effective therapeutics approaches that block oncogenic GNAS induced growth before IPMNs progress towards invasive disease.

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