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Pancreatic Cancer remains the most deadly of the common malignancies, due the lack of a viable early detection method and the limited activity of most drugs. To increase our basic understanding of this disease and advance medical approaches, we have recently co-developed mouse and human pancreatic cancer organoid model systems. Organoid cultures can be robustly prepared from either normal pancreatic ducts or any stage of neoplasia, including preinvasive carcinomas. Additionally, orthotopically transplanted neoplastic organoids remarkably demonstrate cellular plasticity and model the progression of pancreatic cancer from a low-grade preinvasive carcinoma to an invasive and metastatic carcinoma over several months. Thus, the in vitro and in vivo organoid models provide a platform to explore new diagnostic and therapeutic strategies, facilitate the systematic analysis of neoplastic biochemical cascades, and also enable the dissection of tumor microenvironment interactions. The organoid series have allowed us to query the function of important mediators of pancreatic cancer oncogenesis. Indeed, we have found that Nrf2, a principal regulator of redox metabolism, maintains proliferation in KRAS mutant pancreatic ductal cells by lowering the levels of reactive oxygen species to promote protein translation, providing new therapeutic approaches for pancreatic cancer. Additionally, we have used the organoid series to identify new biomarkers of early pancreatic cancer. Finally, the co-culture of organoids with pancreatic stellate cells promotes the activation of each cell type and results in the production of extracellular matrix. Therefore, organoids promise to expand our knowledge of this deadly malignancy and should accelerate the development of new diagnostic and therapeutic approaches.
David Tuveson, M.D., Ph.D.
Director, CHSL Cancer Center
Cold Spring Harbor Laboratory
12:00 pm at Van Andel Institute
Conference Room 3104/3105
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