M. Celeste Simon, Ph.D.

faculty photo
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 cancer cell metabolism, metastasis, inflammation associated tumorigenesis, and cellular responses to oxygen deprivation.

Key words: metastasis, cancer metabolism, hypoxia, mouse models of pancreatic and colorectal cancer, sarcoma, renal cancer.

Description of Research
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 our 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.

Research Techniques
Generation of standard and conditional knockout and transgenic mice, ex vivo developmental models of organogenesis, mouse models of human cancer, gene expression profiling using next generation sequencing, array cGH (the Illumina platform), molecular biology, biochemistry, metabolomics, NMR spectroscopy, mass spectrometry, histology, immunohistochemistry, animal surgery, electron microscopy, and confocal microscopy.

Rotation Projects
Continued analysis of the role of hypoxia-inducible factors, mTOR, autophagy, and ER stress responses in altering tumor metabolism, angiogenesis, recruitment of inflammatory cells, metastasis, 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),
Karin Eisinger-Mathanson (Postdoctoral Fellow),
Alison Grazioli (Clinical Fellow),
Peiwei Huang (Ph.D. Student),
Brian Keith (Adjunct Professor),
David Lee (Research Specialist),
Kyoung Eun Lee, HHMI Associate (Postdoctoral Fellow),
Bo Li (Postdoctoral Fellow),
Nan Lin (Ph.D. Student),
Vera Mucaj (Ph.D. Student),
Michael Nakazawa (M.D., Ph.D. Student),
Joshua Ochoski (Postdoctoral Fellow),
Bo Qiu (M.D., Ph.D. Student),
Danielle Sanchez (Ph.D. Student),
Michele Spata (Research Specialist),

Selected Publications

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 In press, 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.

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Last updated: 08/27/2014
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