M. Celeste Simon, Ph.D.

faculty photo
Arthur H. Rubenstein, MBBCh Professor
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.

Sites of inflammation frequently become hypoxic due to vascular damage, edema, and heightened metabolic activity of bacteria and infiltrating immune cells. Because acute and chronic inflammation predispose individuals to pancreatic and colorectal cancer, we are currently defining how hypoxia provides a connection between inflammation and these GI-related malignancies. We have previously shown that low O2 levels render pancreatic and colonic tissue more “permissive” for neoplastic initiation and progression, and now study how oxygen availability influences the recruitment of immune cells, such as B cells, T cells, macrophages and NK cells to tumors of the pancreas, colon and connective tissues, like undifferentiated pleomorphic sarcoma. Of note, we have recently determined that B cells play a more essential role in pancreatic cancer progression than previously appreciated. This observation has launched 3-4 multi-center clinical trials using B cell inhibitors in conjunction with standard of care, such as gemcitabine and abraxane.

Research Techniques
Generation of standard and conditional knockout and transgenic mice, ex vivo 3D organotypic culture, TCGA data mining, bioinformatics, mouse models of human cancer, gene expression profiling using next generation sequencing, array cGH (the Illumina SNP platform), molecular biology, biochemistry, metabolomics, NMR spectroscopy, mass spectrometry, histology, immunohistochemistry, animal surgery, electron microscopy, flow cytometry, drug discovery and confocal microscopy.

Rotation Projects
Continued analysis of the role of hypoxia-inducible factors, 2-OG dependent dioxygenases, mTOR, autophagy, and ER stress responses in altering tumor metabolism, recruitment of immune cells, metastasis, and tumor progression. Other projects will focus on cellular oxygen sensing and distinct adaptations provided by HIFs versus other oxygen-consuming enzymatic reactions.

Lab Personnel:

Nicole Anderson (Postdoctoral Fellow),
Jason Godfrey (Ph.D. Student),
Kathy Guo (Research Specialist),
Peiwei Huang Yang (Ph.D. Student),
Brian Keith (Adjunct Professor),
Anne Kennedy (Summer Undergraduate Researcher/ALSF Fellow),
Sanika Khare (Ph.D. Student),
Kyoung Eun Lee (Research Associate),
Pearl Lee (Postdoctoral Fellow),
Fuming Li (Postdoctoral Fellow),
Nan Lin (Ph.D. Student),
Rindert Messiaen (Postdoctoral Fellow),
Romain Riscal (Postdoctoral Fellow),
Danielle Sanchez (Ph.D. Student),
Nicolas Skuli (Senior Research Investigator),
Michele Spata (Research Specialist),
Hong Xie (Ph.D. Student).

Selected Publications

Ochocki, J. D., S. Khare, M. S. Hess, D. Ackerman, B. Qiu, J. I Daisak, A. J. Worth, N. Lin, B. Li, B. Wubbenhorst, T. G. Maguire, K. L. Nathanson, J. C. Alwine, I. A. Blair, I. Nissim, B. Keith, M. C. Simon : Arginase 2 suppresses renal carcinoma progression via biosynthetic cofactor pyridoxal phosphate depletion and increased polyamine toxicity. Cell Metabolism in press, 2018.

Xie, H., C.H.A. Tang, J.H. Song, A. Mancuso, J.R. Del Valle, J. Cao, Y. Xiang, C.V. Dang, R. Lan, D.J. Sanchez, B. Keith, C.C.A. Hu, and M.C. Simon : IRE1alpha RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers. J. Clin. Invest. 128(4): 1300-1316, April 2018 Notes: Highlighted in Science Translation Medicine, Biocentury Innovations.

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

Lee, K.E., M. Spata, L.J. Bayne, E.L. Buza, A.C. Durham, D. Allman, R.H. Vonderheide, and M. C. Simon: Hif1α deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer Discovery 6(3): 256-269, March 2016 Notes: Highlighted in Nature Reviews Cancer, Science Signaling, F1000 Prime.

Lee, K.E., and M.C. Simon: 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 513(7517): 251-255, September 2014 Notes: Highlighted in Nature Reviews Cancer, Cancer Discovery, Nature Reviews Urology, Science Signalling, and the NCI website, "Breakthrough of the Year" NRU.

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 3(10): 1190-1205, October 2013 Notes: Highlighted in Science and Cancer Discovery.

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 27(10): 1115-1131, May 2013 Notes: Highlighted in Nature Reviews Cancer.

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 22(5): 631, November 2012 Notes: Highlighted in Cancer Discovery.

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 12(10): 1007-1013, October 2010 Notes: News and Views, Nature Cell Biology.

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Last updated: 05/21/2018
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