The Lab of Stem-Cell Derived Organoid Models in Pancreatic Diseases and Cancer

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How Do Precancerous Lesions Develop Towards Pancreatic Cancer?

Pancreatic cancer is one of the deadliest diseases in United States, with a 5-year survival of 12% and is considered to be one of the most aggressive types of cancer. When patients are diagnosed early with this disease, treatment with surgery and chemotherapy can improve the 5-year survival by ~44%. However, only about ~12.9% of patients are diagnosed at early stages – before the cancer has metastasized. Therefore, there is a desperate need to develop methods to diagnose pancreatic cancer early.

Pancreatic ductal adenocarcinoma (PDAC) develops in the exocrine compartment of the pancreas, which is comprised of ductal and acinar cells. PDAC is associated with two major types of asymptomatic precancerous lesions - microscopic pancreatic intraepithelial neoplasia (PanINs) and macroscopic mucin-producing cystic neoplasms, namely, intraductal papillary mucinous neoplasms (IPMN). Unlike PanINs, which currently remain clinically undetectable, IPMNs form large cystic mucin-producing neoplasms and can be clinically diagnosed through abdominal imaging. Genomic studies reveal that oncogenic mutations in a G-protein (GNAS) are exclusive to IPMN lesions while KRAS mutations are shared between PanIN and IPMN lesions. However, how IPMNs arise in humans in the context of mutations that are exclusively found in IPMN lesions and what cooperating events promote progression to IPMN-derived PDAC is not known. Resolving how cell of origin affects pathways that govern progression of precancerous lesions will ultimately allow us to develop methods to detect PDAC early, which is arguably the most important goal of pancreatic cancer research.

Our Approach

Using human ductal-like and acini-like pancreatic organoids, generated from human embryonic stem cell-derived pancreatic progenitors, the goal of Desai Laboratory is to uncover how cell lineage tropism regulates oncogene cooperation during the initiation and progression of precancerous lesions, particularly IPMNs. Using a combination of proteomic, genomic, cell biological, and in vivo approaches, our laboratory aims to generate models of IPMN to identify genetic interactions and mechanisms that regulate progression of IPMN to metastatic PDAC.

Our Discoveries

Desai uses human pluripotent stem cells to grow pancreatic ductal and acini-like cells as mini ‘organs’ called – Organoids. This organoid technology provides us with an invaluable tool to investigate cell of origin and mechanisms underlying many pancreatic diseases, including pancreatic cancer.

Desai discovered that in the ductal organoids, oncogenic GNAS induced PKA-dependent IPMN-associated phenotypes. Surprisingly, the oncogene also increased cell proliferation through a PKA- independent pathway, demonstrating a cell-type specific phenotype in ductal epithelia.

Desai established long-term stable cultures of oncogenic GNAS-expressing ductal organoids as a platform to elucidate how oncogenic GNAS induces PKA-independent proliferation and identify regulators of IPMN progression.

JOIN THE LAB

We are always seeking thoughtful, honest, hardworking, and ambitious new lab members! Come help us build our new research team!

Prospective Postdoctoral Fellows
Please feel free to contact Ridi by email.

Prospective Graduate Students
If you are interested in our research, please feel free to come talk to me either in person or via email.

Undergraduate Students
If research is something you would like to explore and would get a sneak preview, come talk to us!

Everyone is Welcome here!
Our lab seeks to develop a research team with people from diverse backgrounds. If you love organoids, microscopy, pancreatic diseases, stem cells, cancer, mouse models, please connect with us!

 
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