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M. Celeste Simon

University of Pennsylvania, Philadelphia, PA 19104

Wednesday, October 23, 10:05 - 10:30

Hypoxia signal pathway cross-talk in cancer

Solid tumors exhibit heterogeneous microenvironments, often characterized by limiting concentrations of oxygen (O2), glucose, and other nutrients. How oncogenic mutations alter stress response pathways, metabolism, and cell survival in the face of these challenges is incompletely understood. Here we report that constitutive mammalian target of rapamycin complex 1 (mTORC1) activity renders hypoxic cells dependent on exogenous desaturated lipids, as levels of de novo synthesized unsaturated fatty acids are reduced under low O2. Specifically, we demonstrate that hypoxic Tsc2-/- (tuberous sclerosis complex 2-/-) cells deprived of serum lipids exhibit a magnified unfolded protein response (UPR) but fail to appropriately expand their endoplasmic reticulum (ER), leading to inositol-requiring protein-1 (IRE1)-dependent cell death that can be reversed by the addition of unsaturated lipids. UPR activation and apoptosis were also detected in Tsc2-deficient kidney tumors. Importantly we observed this phenotype in multiple human cancer cell lines and suggest that cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance lipid and protein synthesis due to a critical limitation in desaturated lipids.


M. Celeste Simon, Ph.D. is the Scientific Director of the Abramson Family Cancer Research Institute at the Perelman School of Medicine at the University of Pennsylvania. She is also an Investigator of the Howard Hughes Medical Institute. She received her bachelor's degree from Miami University and completed a Ph.D. in biochemistry at Rockefeller University in 1985. She conducted postdoctoral research with Joseph Nevins at Rockefeller and then with Stuart Orkin at Harvard Medical School. She became an Assistant Professor of Medicine and Molecular Genetics and Cell Biology at the University of Chicago in 1992. In a National Competition, she was named an Assistant Investigator of the Howard Hughes Medical Institute in 1994.

In 1999, she moved to the University of Pennsylvania School of Medicine and was one of the founding laboratories of the newly formed Abramson Family Cancer Research Institute (AFCRI) there. She was promoted to Associate Professor in 1999, and full Professor in 2006. In 2007, she became the Scientific Director of the AFCRI. Dr. Simon's research is focused on how cells sense and respond to changes in the availability of molecular oxygen. This impacts normal development, physiology, and numerous diseases, such as the growth of solid tumors. The Simon Laboratory is studying how O2 sensing impacts tumor angiogenesis, metabolism, and metastasis, and overall disease progression. She is studying both animal models and cancer patients with the ultimate goal of developing novel strategies to treat tumors such as pancreatic cancer, soft tissue sarcoma, colorectal cancer, and lung adenocarcinoma. Dr. Simon currently directs a laboratory of 20 individuals, including graduate students, postdoctoral fellows, clinical fellows, and research technicians. The AFCRI employs 400 researchers working in roughly 30 independent laboratories. Dr. Simon has received numerous awards recognizing her research, such as the Stanley N. Cohen Award for Biomedical Research and the Elliot Osserman Award from the Israel Cancer Research Fund.


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