Stem-cell Derived Organoids to Model and Dissect Mechanisms of Pancreatic Diseases

Wednesday, April 22, 2026

2:30 PM-4:00 PM

BIOMED Seminar

Title:
Stem-cell Derived Organoids to Model and Dissect Mechanisms of Pancreatic Diseases

Speaker:
Ridhdhi Desai, PhD
Assistant Professor
Biochemistry and Molecular Biology
College of Medicine
Drexel University 

Details:
Pancreatic ductal adenocarcinoma (PDAC) is the third deadliest cancer, causing ~52,000 deaths each year in United states. In comparison to all cancers, patients with PDAC have the worst 5-year survival of 13%, largely due to late diagnosis. PDAC is associated with currently the only clinically detectable  asymptomatic precancerous lesion called intraductal papillary mucinous neoplasms (IPMN). However, very little is known about how IPMNs develop, why some IPMN lesions progress to PDAC and some do not, and how to prevent their progression. Whole-genome sequencing efforts have identified GNAS, a G-protein involved in GPCR signaling, to be exclusively mutated in 66% of IPMN lesions. Although genetically engineered mouse models (GEMMs) have provided some insights into the function of GNAS in the initiation of IPMN, cell-type specific mechanisms by which oncogenic GNAS affects IPMN development are limited, largely due to challenges in maintaining human acinar cells in culture.
 
To address this limitation, we have developed a human pancreatic ductal and acini organoid model system from embryonic and pluripotent stem cells to investigate mechanisms regulating GNASR201C-induced IPMNs. Using this strategy, we show that expression of GNASR201C in human ductal organoids recapitulates many features of IPMN including lumen expansion and mucin secretion. Surprisingly, expression of GNASR201C also induces aberrant cell proliferation in a PKA-signaling independent manner in short-term and stable, long-term cultures of ductal organoids, but not in acinar organoids. We also show that co-expression of oncogenic KRASG12V and GNASR201C retained PKA-independence in ductal organoids and PKA-dependence in acinar organoids for stimulation of cell proliferation. Delving into the mechanism, our preliminary results indicate that oncogenic GNAS potentiates MAPK signaling independent of exogenous EGF to promote ductal cell proliferation. BioID-based proteomic, RNA-seq-based genomic, and kinase inhibitor-based functional studies reveal an intriguing possibility that oncogenic GNAS interacts with proteins involved in the ubiquitin proteosome system to regulate MAPK signaling. Altogether, we establish a platform to investigate mechanisms by which oncogenic GNAS promotes PKA-independent proliferation and demonstrate the utility of stem cell-derived pancreatic organoid model for investigating cell lineage-specific mechanisms in the initiation and progression of human pancreatic cancer.

Biosketch:
Ridi's interest in scientific research began during her undergraduate study at University of Toronto, where she used yeast cells to identify non-essential genes that increase the frequency of spontaneous direct-repeat recombination. During her graduate research in the lab of Dr. Ulrich Tepass, Ridi became fascinated with epithelial biology, where she used Drosophila genetics to discover a role for how alpha-catenin mediates connections between cell adhesion molecules and actin cytoskeleton during morphogenesis. 

After finishing her PhD at the University of Toronto, Ridi transitioned to mammalian biology with a focus on epithelial-derived cancers. During her postdoc in the lab of Senthil Muthuswamy Lab (BIDMC, Harvard Medical School) using human stem cell derived organoid models of pancreatic ductal and acini cells, she identified a cell-type specific role for oncogene activity in precancerous lesions of pancreatic cancer.