|Name:||M. Celeste Simon, Ph.D.|
|Title/Titles:||Scientific Director and Investigator,
Abramson Family Cancer Research Institute
Professor, Cell and Developmental Biology
University of Pennsylvania School of Medicine
simon lab Overview
Dr. Simon obtained a bachelor’s degree at Miami University (Oxford, Ohio) in 1977, and
a M.S. in Microbiology at Ohio State University in 1980. Her Ph.D. in Biochemistry was
obtained from Rockefeller University in 1985. She conducted postdoctoral research in the
laboratories of Dr. Joseph Nevins (Rockefeller University) and Dr. Stuart Orkin (Harvard Medical
School). As a Howard Hughes Associate in Dr. Orkin’s laboratory, she began her work on
hematopoietic development using mouse embryonic stem cells as a model for differentiation.
Her first faculty position was at the University of Chicago (1992), Department of
Medicine, where she continued her studies on hematopoiesis. She became an assistant
investigator of the Howard Hughes Medical Institute in 1994 in a national competition that
appointed seventeen junior faculty to the HHMI. Focusing on the role of the PU.1 transcription
factor in specifying hematopoietic cell fate, Dr. Simon definitively showed that PU.1 is essential
for the development of macrophages, neutrophils, B lymphocytes, T lymphocytes, and mast
cells. At this time, she developed an interest in angiogenesis and how hematopoiesis and
angiogenesis are tightly linked in the developing mouse embryo. She turned her attention to the
role of oxygen (O2) availability in regulating hematopoiesis and angiogenesis and studied
mouse knockouts of the hypoxia inducible factor (HIF) signaling pathways. These studies show
that the naturally low O2 environment of the developing embryo regulates blood cell, blood
vessel, placental, and cardiac development via HIF. In 1999, she joined the new Abramson
Family Cancer Research Institute (AFCRI) at the University of Pennsylvania School of Medicine
and is now a Professor there. She was promoted to Associate Investigator (HHMI) in 2000, and
full Investigator in 2005. On September 1, 2007, she became the Scientific Director of the
The AFCRI Simon laboratory is currently studying the impact of the hypoxic tumor microenvironment on disease progression. Due to vascular insufficiency, solid tumors frequently harbor domains where cells have limited access to oxygen and blood-borne nutrients. Molecular oxygen (O2) is an essential nutrient serving as a key substrate for mitochondrial ATP production and numerous intracellular biochemical reactions. The maintenance of oxygen homeostasis is therefore essential for the survival of most prokaryotic and eukaryotic species. O2 deprivation (hypoxia) triggers complex adaptive responses at the cellular, tissue, and organismal levels to match O2 supply with metabolic and bioenergetic demands. In the face of hypoxic stress, mammalian cells temporarily arrest cell cycle progression, reduce energy consumption, and secrete survival and pro-angiogenic factors. These events are coordinated by engaging multiple, evolutionarily conserved molecular responses mediated by the hypoxia-inducible factor (HIF) transcriptional regulators, mTOR signaling, autophagy, and the endoplasmic reticulum (ER) stress responses. Whereas severe hypoxia is observed in many pathological situations, including tissue ischemia, arthritis, wound healing, inflammation, and solid tumors, it is important to note that developing embryos and adult tissues also harbor natural O2 gradients that impact multiple cellular phenotypes, including quiescence, macromolecular synthesis, differentiation, and migration. The overall goal of Dr. Simon’s research is to elucidate the molecular mechanisms by which changes in O2 and nutrient availability modulate normal tissue homeostasis and mammalian pathology, with a particular focus on cancer cell metabolic reprogramming, metastasis, and the link between chronic inflammation and cancer predisposition.
Because a solid tumor cannot grow unless it acquires new blood vessels from surrounding host tissues, the HIFs are necessary for tumor progression, given that they regulate blood vessel formation. Mutations in multiple tumor suppressor genes lead to HIF stimulation, tumor angiogenesis, and tumor growth. Our studies have shown that the HIFs are also clearly important for tumor metastasis. We have created conditional alleles of HIF-1alpha, HIF-2alpha, and the gene encoding their common dimerization partner ARNT to determine how they affect tumor growth in the kidney, pancreas, muscle, and intestine. This will allow us to genetically dissect the role of HIFs in all phases of tumor progression: latency, size, altered cell metabolism, vascularity, and metastasis. In addition to studying the role of HIFs in mouse models, we are also evaluating their activity in human patient samples, focusing on specimens acquired from individuals with renal clear cell carcinoma, sarcoma, pancreatic ductal adenocarcinoma, and colorectal cancer. Cancer cell metabolic reprogramming is also impacted by variable O2 and nutrient levels in solid tumors. Finally, HIF-regulated adaptations within the tumor must be integrated with other oxygen-sensing pathways, such as mTOR, autophagy, and the ER unfolded protein response. Our ongoing studies will delineate each of these pathways in cancer cell metabolic adaptations, hoping to further exploit them for therapeutic benefit.
Dr. Simon presently has eight postdoctoral fellows, five predoctoral fellows, one undergraduate student, and two research technicians in her research group. The laboratory is currently funded by two NIH R01s, one NIH P01, the AACR, the AFCRI, and multiple predoctoral and postdoctoral training fellowships. Dr. Simon has received numerous awards for her research such as the Cancer Research Foundation Young Investigator Award and Stanley M. Cohen Award for Biomedical Research just to name a few. She was a Howard Hughes Medical Institute Investigator for over 20 years, and is currently a member of the Board of Directors of the American Association for Cancer Research, the Chair of the NIH Tumor Microenvironment Study Section, and the Editorial Board of various cancer related journals, such as Cell Metabolism, Cancer Discovery, the Journal of Clinical Investigation, and Oncogene. In 2014, Dr. Simon was elected a Fellow of the American Academy of Arts of Sciences.
Li, B., B. Qiu, D. S. M. Lee, Z. E. Walton, J. D. Ochocki, L. K. Mathew, A. Mancuso, T. P. F. Gade, I. Nissim, B. Keith, and M. C. Simon : Fructose-1, 6-bisphosphatase opposes renal carcinoma progression. Nature(Highlighted in Nature Reviews Cancer, Cancer Discovery, Nature Reviews Urology, Science Signalling, and the NCI website) 513: 251-255, 2014.
Eisinger-Matheson, T.S., M. Zhang, Q. Qiu, N.Skuli, M.S. Nakazawa, T. Karakasheva, V. Mucaj, J.E. Shay, L. Stangenberg, N. Sadri, E. Pure, S.S. Yoon, D. G. Kirsch, and M.C. Simon: Hypoxia-dependent modification of collagen networks promote sarcoma metastasis. Cancer Discovery (Highlighted in Science) 3: 1190-1205, 2013.
Young, R. M., D. Ackerman, Z.L. Quinn, A. Mancuso, M. Gruber, L. Liu, D.N. Giannoukos, E. Bobrovnikova-Marjon, J.A. Diehl, B. Keith, and M.C. Simon: Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tunor-like stress. Genes and Development (Highlighted in Nature Reviews Cancer) 27: 1115-1131, 2013.
Qing, G., B. Li, A. Vu, N. Skuli, Z. Walton, X. Liu, P.A. Mayes, D. R. Wise, C. B. Thompson, J. M. Maris, M. D. Hogarty, and M. C. Simon: ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell (Highlighted in Cancer discovery) 22: 631, 2012.
Young, RM and MC Simon: Untuning the tumor metabolic machine: HIF-a: pro- and antitumorigenic? Nat. Med. 18: 1024-1025, 2012.
Skuli, N., A. J. Majmundar, B. L. Krock, R. C. Mesquita, L. K. Mathew, Z. L. Quinn, A. Runge, L. Liu, M. N. Kim, J. Liang, S. Schenkel, A. G. Yodh, B. Keith, M. C. Simon : Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes. J. Clin. Invest. 122: 1427-1423, 2012.
Keith, B., R. S. Johnson, and M. C. Simon : HIF-1α and HIF-2α: sibling rivalry in hypoxic tumor growth and progression. Nature Reviews Cancer 12: 9-22, 2012.
Imtiyaz, H. Z., E. P. Williams, M. M. Hickey, S. A. Patel, A. C. Durham, L. J. Yuan, R. Hammond, P. A. Gimotty, B. Keith, and M. C. Simon: Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest. Previewed in SciBX: Science-Business exchange, Nature Reviews Cancer, and Cancer Research. 120: 2699-2714, 2010.
Mazumdar, J., W. T. O’Brien, R.S. Johnson, J. C. LaManna, J. C. Chavez, P. S. Klein, and M. C. Simon : O2 regulates stem cells through Wnt/β-catenin signaling. Nature Cell Biology. (News and Views, Nature Cell Biology.) 12: 1007-1013, 2010.
Gordan, J. D., P. Lal, V. R. Dondeti, R. Letrero, K. N. Parekh, C. E. Oquendo, R. A. Greenberg, K. T. Flaherty, W. K. Rathmell, B. Keith, M. C. Simon: HIF-α effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell. Corresponding author. Previewed in Cancer Cell. 14: 435-446, 2008.