|Name:||M. Celeste Simon, Ph.D.|
|Title/Titles:||Scientific Director and Investigators,
Abramson Family Cancer Research Institute
Investigator, Howard Hughes Medical Institute
Professor, Cell and Developmental Biology
University of Pennsylvania School of Medicine
simon lab Overview
Our laboratory studies responses to changes in oxygen availability. Solid tumors frequently develop areas subjected to hypoxia, hypoglycemia, and decreased levels of growth factors due to vascular insufficiency. Although most tumors acquire blood vessels due to neoangiogenesis or vessel co-option, tumor blood vessels are frequently dysfunctional, resulting in poorly perfused regions. Therefore, tumor cell adaptations to these stresses contribute to malignant progression. We have studied hypoxia-inducible factors (HIFs), and how they regulate tumor cell metabolism, angiogenesis, inflammatory cell recruitment, epithelial-to-mesenchymal cell transitions, and metastasis. Cell-based assays provide insight into HIF-regulated mechanisms that contribute to these properties. We have now modeled a variety of diseases in gene-targeted mice, and more recently translated our findings to patient samples from individuals afflicted with renal cell carcinoma, glioblastoma, neuroblastoma, and lung adenocarcinoma. We have also studied HIF-independent pathways such as the mTOR- and AMPK-regulated pathways to determine how they promote cellular adaptation to low O2.
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
Dr. Simon’s current research interests include understanding the molecular basis of how
hypoxia and HIF regulate cardiovascular differentiation and stem cell function. Mouse models
have been developed to probe HIF regulation of tumor development (e.g. lung
adenocarcinomas, hepatocellular carcinomas, and renal cancers). She is also interested in how
O2 levels are sensed by cells and tissues. A new project focuses on how O2 availability
regulates protein translation control. Protein translation is an ATP-rich process within the cell
and must be inhibited as O2 and ATP levels simultaneously decrease. All of these studies will
benefit our understanding of how O2 availability regulates the unique physiology of solid tumors
and hopefully be exploited for novel therapies to inhibit tumor cell survival, tumor angiogenesis,
and tumor metastasis.
Dr. Simon currently has seven postdoctoral fellows, seven predoctoral fellows, two
undergraduate students, and two technicians in her laboratory. She is currently funded by the
HHMI, one NIH R01, one NIH P01, and the AFCRI. 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.
Keith, B., and M.C. Simon: Hypoxia-inducible factors, stem cells, and cancer. Cell 129: 465-472, 2007.
Mazumdar, J. W., T. O'Brien, R. S. Johnson, P. S. Klein, and M. C. Simon: O2 regulates stem cells through Wnt Beta-catenin signaling. Nat Cell Biol manuscript submitted, 2010.
Simon, M Celeste. Keith, Brian.: The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol 9(4): 285-96, Apr 2008.
Gordan, John D., Lal, Priti, Dondeti, Vijay R., Letrero, R., Parekh, Krishna N., Oquendo, C.E., Greenberg, Roger A., Keith T. Flaherty, Rathmell, W.K., Keith, Brian, Simon, M. Celeste*, and Nathanson, Kate L.: HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14: 435-446, 2008 Notes: *Corresponding author. Previewed in this issue.
Skuli, N., J. Liu, A. Runge, T. Wang, L. Yuan, S. Patel, L. Iruela-Arispe, M. C. Simon, and B. Keith: Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis. Blood 114: 469-477, May 2009.
Bertout J. A., Majmundar A. J., Gordan J. D., Lam J. C., Ditsworth D., Keith B., Brown E. J., Nathanson K. L., Simon M. C.: HIF2alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc Natl Acad Sci USA 106: 14391-14396, Aug 2009.
Hickey M. M., Richardson T., Wang T., Mosqueira M., Arguiri E., Yu H., Yu Q. C., Solomides C. C., Morrisey E. E., Khurana T. S., Christofidou-Solomidou M., Simon M. C.: The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. J Clin Invest 120: 827-839, Feb 2010.
Imityaz, H. Z., E. P. Williams, M. M. Hickey, S. A. Patel, A. C. Durham, B. Keith, and M. C. Simon: Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest 120: 2699-2714, 2010 Notes: Previewed in SciBX: Science Business Exchange.
Mazumdar, J., M. M. Hickey, D. K. Pant, A. Durham, A. Sweet-Cordero, A. Vachani, T. Jacks, L. A. Chodosh, J. L. Kissil, M. C. Simon, and B. Keith: HIF-2alpha deletion promotes Kras-driven lung tumor development. Proc Natl Acad Sci USA in press, 2010 Notes: Previewed in Nature Reviews Cancer.
Gordan, John D. Bertout, Jessica A. Hu, Cheng-Jun. Diehl, J Alan. Simon, M Celeste.: HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11(4): 335-47, Apr 2007 Notes: Previewed in Nature Reviews Cancer.