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M. Celeste Simon, Ph.D.

M. Celeste Simon, Ph.D.

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Professor of Cell and Developmental Biology
Department: Cell and Developmental Biology
Graduate Group Affiliations

Contact information
Howard Hughes Medical Institute
The Abramson Family Cancer Research Institute
Department of Cell and Developmental Biology
University of Pennsylvania School of Medicine
456 BRB II/III
421 Curie Boulevard
Philadelphia, PA 19104-6160
Office: 215-746-5532
Fax: 215-746-5511
Education:
B.A. (Microbiology)
Miami University, 1977.
M.S. (Microbiology)
Ohio State University, 1980.
Ph.D. (Molecular Biology)
The Rockefeller University, 1985.
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Description of Research Expertise

Research Interests
Our laboratory studies stem cells, angiogenesis, inflammation, tumorigenesis, cancer cell metabolism, and cellular responses to oxygen deprivation.

Key words: stem cells, angiogenesis, hematopoiesis, cancer, metabolism, hypoxia, tumor suppressors, mouse models of human malignancy.

Description of Research
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 bioenergetics 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, and the endoplasmic reticulum (ER) stress response. 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 our research is to elucidate the molecular mechanisms by which changes in O2 availability modulate normal tissue homeostasis and mammalian pathology, with a particular focus on cancer progression, metabolic regulation, and stem cell function.

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. By identifying the underlying molecular mechanisms for HIF's promotion of blood vessel growth and tumor cell survival, we hope to develop procedures that will “cut off” the tumor’s O2 supply and diminish the cancer cell’s ability to metastasize. 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 lung, 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, glioblastoma multiforme, sarcoma, and neuroblastoma. 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 these pathways in cancer cell metabolic adaptations, hoping to further exploit them for therapeutic benefit.

The maintenance, differentiation, and function of embryonic and adult stem cells are influenced by numerous complex signals provided by their immediate microenvironment. One important microenvironmental factor for stem/progenitor cell biology is actually molecular O2. We have conclusively shown that HIFs regulate how stem cells adapt to changes in O2 availability, and continue to unravel their role in multiple developmental processes. We have determined that HIFs directly regulate stem cell quiescence, proliferation, and differentiation by modulating critical pathways like those involving Oct4, Wnt, Notch, and c-Myc. Genetic deletion of HIF-1alpha and HIF-2alpha in mice has revealed their essential role in maintaining stem cells of the bone marrow, skin, muscle, and germline. We hypothesize that some long-lived stem cells occupy relatively O2-starved regions to maintain quiescence and protect the integrity of their genome. Moreover, stem/progenitor cells migrate through natural O2 gradients as they adopt distinct cell fates, and are therefore also influenced by HIFs as they mature. Finally, the effects of O2 availability and HIFs on normal stem cells are likely be to co-opted in tumors dependent on so-called “cancer stem cells”. Our ongoing studies will further evaluate the impact of O2 availability and the HIFs on normal and malignant stem cell populations.


Research Techniques
Generation of standard and conditional knockout and transgenic mice, ES cell technology, stem cell biology, embryology, ex vivo developmental models of organogenesis, mouse models of human cancer, gene expression profiling using Affymatrix microarrays, array cGH (the Illumina platform), genome wide association studies, molecular biology, biochemistry, metabolomics, NMR spectroscopy, histology, immunohistochemistry, in situ hybridization, animal surgery, electron microscopy, confocal microscopy, and live cell imaging.

Rotation Projects:
Continued analysis of the role of hypoxia-inducible factors, mTOR, autophagy, metabolism, and tumor suppressors in stem cell function, angiogenesis, hematopoiesis, and tumor progression. Other projects will focus on cellular oxygen sensing and distinct adaptations provided by HIF-1 versus HIF-2.

Lab Personnel:

Daniel Ackerman (Postdoctoral Fellow),
Ruchi Amin (HHMI Medical Fellow),
Karin Eisinger-Mathanson (Postdoctoral Fellow),
Terence Gade (Clinical Fellow),
Sharon Gerecht (Visiting Professor),
Brian Keith (Adjunct Professor),
David Lee (Research Specialist),
Kyoung Eun Lee, HHMI Associate (Postdoctoral Fellow),
Bo Li (Postdoctoral Fellow),
Nan Lin (Ph.D. Student),
Lijoy Mathew, HHMI Associate (Postdoctoral Fellow),
Vera Mucaj (Ph.D. Student),
Michael Nakazawa (M.D., Ph.D. Student),
Joshua Ochoski (Postdoctoral Fellow),
Bo Qiu (M.D., Ph.D. Student),
Navid Sadri (Clinical Fellow)
Jessica Shay (M.D., Ph.D. Student),
Michele Spata (Research Specialist),
Elizabeth Tucker (Undergraduate Student)

Selected Publications

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 Regina M, Ackerman Daniel, Quinn Zachary L, Mancuso Anthony, Gruber Michaela, Liu Liping, Giannoukos Dionysios N, Bobrovnikova-Marjon Ekaterina, Diehl J Alan, Keith Brian, Simon M Celeste: Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. Genes & development 27(10): 1115-31, May 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.

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.

Bertout, J. A., A. J. Majmundar, J. D. Gordan, J. C. Lam, D. Ditsworth, B. Keith, E. J. Brown, K. L. Nathanson, and M. C. Simon : HIF2α inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc. Natl. Acad. Sci. USA 106: 14391-14396, 2009.

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.

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.

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Last updated: 04/11/2014
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