M. Celeste Simon, Ph.D.

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

Contact information
Scientific Director
The Abramson Family Cancer Research Institute
Department of Cell and Developmental Biology
University of Pennsylvania Perelman School of Medicine
Room 456 BRB II/III
421 Curie Boulevard
Philadelphia, PA 19104-6160
Office: 215-746-5532
Fax: 215-746-5511
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, tumor immunology, metastasis, and cellular responses to oxygen deprivation.

Key words: metastasis, cancer metabolism, immunology, hypoxia, mouse models of pancreatic, colorectal, liver, sarcoma, and 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),
Ankita Bansal (Postdoctoral Fellow),
Peiwei Huang (Ph.D. Student),
Brian Keith (Adjunct Professor),
Sanika Khare (Ph.D. Student),
Roy Lan (Undergraduate Researcher),
Kyoung Eun Lee (Research Associate),
Pearl Lee (Postdoctoral Fellow),
Fuming Li (Postdoctoral Fellow),
Nan Lin (Ph.D. Student),
Richard Maduka (HHMI Medical Fellow),
Vivek Nimgaonker (Research Specialist),
Joshua Ochoski (Postdoctoral Fellow),
Danielle Sanchez (Ph.D. Student),
Michele Spata (Research Specialist),
Hong Xie (Ph.D. Student).

Selected Publications

Nakazawa, M.S., T.S.K. Eisinger-Mathason, N. Sadri,J.D. Ochocki, T. Gade, and M.C. Simon: Epigenetic re-expression of HIF-2a suppresses soft tissue sarcoma growth. Nature Comm. 7: 10539, 2016.

Lee, K. E., M. Spata, L. J. Bayne, E. L. Buza, A. C. Durham, D. Allman, R. H. Vonderheide, and M. C. Simon: Hif1a deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer Discovery (Highlighted in Nature Reviews Cancer, Cancer Discovery and Faculty of 1000). 6: 256-269. 2016 Notes: Highlighted in Nature Reviews Cancer, Science Signaling, F1000 Prime.

Lee, K. E., and Simon, M. C. : Snapshot: Hypoxia-Inducible Factors. Cell 163: 1288-1288, November 2015.

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) "Breakthrough of the Year", NRU. 513(7517): 251-255, September 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(10): 1190-1205, October 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(10): 1115-1131, 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(5): 631, November 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(8): 2699-2714, August 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(10): 1007-1013, October 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(6): 435-446, December 2008.

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Last updated: 05/26/2016
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