David Tuveson (Cold Spring Harbor)
MolBio Seminar Series
David Tuveson MD, PhD, is Professor and the Deputy Director of the Cancer Center at Cold Spring Harbor Laboratory. Dr. Tuveson is also the Director of Research for the Lustgarten Pancreatic Cancer Research Foundation, and cares for pancreatic cancer patients at MSKCC. Dr. Tuveson received his medical and graduate training at Johns Hopkins, followed by clinical training at Brigham and Women’s Hospital and Dana-Farber/Harvard Cancer Center. While at Dana-Farber, Dr. Tuveson co-developed Imatinib with Dr. Demetri for GIST patients. Following post-doctoral training with Tyler Jacks at MIT, Dr. Tuveson directed laboratories at the University of Pennsylvania and Cambridge University prior to moving to Cold Spring Harbor in 2012. Dr. Tuveson’s laboratory established mouse models of pancreatic cancer to explore the biology of the disease and identify new therapeutic and diagnostic approaches. At CSHL he leads the Cancer Therapeutics Initiative.
Progress in Pancreatic Cancer Modeling
Although ductal pancreatic cancer remains highly lethal, recent laboratory progress in demystifying this disease have provided several new therapeutic approaches. Somatically mutant KRAS is present in most cases of pancreatic cancer, and mouse models have clarified the role of oncogenic Kras in neoplastic initiation and progression. Surprisingly, methods that target canonical MAPK/PI3K effector pathways have been only partially successful in mouse models.
Therefore, we have investigated additional aspects of pancreatic tumor biology that contribute to disease pathogenesis. Chief contributors to the unusual desmoplastic structure and drug-refractory nature of pancreatic tumors are activated pancreatic stellate cells. PSCs assume a fibroblastic morphology and function during tumor evolution, resulting in a collagen- and glycosaminoglycan-rich extracellular matrix that prevents angiogenesis and compresses the resident vasculature such that drug delivery is impeded. Additionally, PSCs secrete many products including CTGF that promote neoplastic cell survival and thereby suppress therapeutic responses to classical and targeted agents. Finally, PSCs secrete CxCl12, which repels T lymphocytes from neoplastic cells to prevent immune clearance. Despite the existence of these biophysical, biochemical and immune therapeutic resistance mechanisms, they also provide avenues to circumvent each barrier for improved outcomes.
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