Faculty

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
Arthur H. Rubenstein, MBBCh, Professor
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
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, tumor immunology, metastasis, and responses to oxygen/nutrient deprivation in the tumor microenvironment.

Key words: hypoxia; cancer metabolism; immunology; metastasis; in vivo and ex vivo models of pancreatic, liver, and renal cancer, and sarcoma.

Description of Research:
Due to vascular insufficiency, solid tumors frequently harbor domains where cells have limited access to oxygen and blood borne nutrients (glucose, amino acids, lipids, etc.). Molecular oxygen (O2) is an essential nutrient serving as a key substrate for mitochondrial ATP production and numerous intracellular biochemical reactions. O2 deprivation (hypoxia) triggers complex adaptive responses at the cellular, tissue, and organismal levels to match O2 supply with metabolic and bioenergetic demands. Moreover, if cells are deprived of oxygen, they are very likely to be simultaneously limited for circulating nutrients like glucose etc. In the face of metabolic stress, mammalian cells temporarily arrest cell cycle progression, reduce energy consumption, and secrete survival and proangiogenic factors. These events are coordinated by engaging multiple evolutionarily conserved molecular adaptations, mediated by metabolic transitions, hypoxia inducible factor (HIF) transcriptional regulators, mTOR signaling, autophagy, and endoplasmic reticulum (ER) stress responses. The overall goal of our research is to elucidate molecular mechanisms whereby changes in O2 and nutrient availability modulate normal tissue homeostasis and mammalian pathology, with a particular focus on cancer cell metabolic reprogramming, metastasis, and interactions between malignant and infiltrating immune cells.

Sites of infection or inflammation frequently become hypoxic due to blood vessel damage, tissue edema, and heightened metabolic activity of pathogens and infiltrating immune cells. We have previously shown that low O2 levels render inflamed pancreatic and liver tissue more “permissive” for neoplastic initiation and progression, and now study how O2/nutrient availability influences the recruitment and functionality of immune cells (such as T cells, macrophages, dendritic cells, neutrophils, B cells, and NK cells) into tumors of the pancreas, liver, kidney, and connective tissues that generate sarcomas. We are particularly interested in how changes in malignant cell metabolism allow pancreatic and liver cancer cells to “outcompete” for critical nutrients, such as arginine, glutamine, and lipids that influence cytotoxic T cell and myeloid cell activity. These “metabolic symbioses” between tumor cells and other cells within the microenvironment (immune cells, endothelial cells, fibroblasts) need to be further characterized to enhance the efficacy of targeted and immunotherapies and expand the number of patients deriving benefit from these approaches. For example, we recently determined that B cells play a more essential role in pancreatic cancer progression than previously appreciated and influence cytotoxic T cell activity. This observation launched multi-site clinical trials using B cell inhibitors in conjunction with standard of care, such as gemcitabine and abraxane. We have also learned that kidney cancers accumulate cholesterol, which promotes T cell dysfunction in the tumor microenvironment.

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. We have recently shown that HIFs (and metabolic changes they coordinate) are also clearly important for tumor metastasis. In addition to studying HIFs and metabolism in genetically engineered mouse models, we are also evaluating transcriptomic, epigenetics, and metabolomics in human patient samples, focusing on specimens acquired from individuals with renal clear cell carcinoma, sarcoma, pancreatic ductal adenocarcinoma, and liver cancer. The goal is to integrate our understanding of metabolic adaptations with documented changes in intracellular signaling, organelle function, and genome-wide mutations. Cancer cell metabolic reprogramming is directly impacted by variable O2 and nutrient levels in solid tumors, and must be integrated with other processes, such as changes in the epigenome. Our ongoing studies will delineate each of these pathways, hoping to further exploit them for therapeutic benefit.

Research Techniques:
Generation of genetically engineered and patient derived xenotransplanted mice, CRISPR-based gene editing and genome-wide screens, ex vivo 3D organotypic culture, integrated “omics” characterization of human tumors, TCGA data mining, bioinformatics, next generation sequencing, ChIP-Seq, epigenetics, proteomics, array cGH (the Illumina SNP platform), molecular biology, biochemistry, metabolomics, NMR spectroscopy, mass spectrometry, histology, immunohistochemistry, multiplexed immunofluorescence, animal surgery, electron microscopy, flow cytometry, drug discovery and confocal microscopy. Whatever it takes!!

Rotation Projects:
Continued analysis of altered tumor metabolism, growth, recruitment of immune cells, and metastasis that drive disease. We are particularly interested in how tumor cells and endothelial cells, immune cells, and fibroblasts of the microenvironment “compete” for limited O2 and nutrients available and how this influences tumor immunity. Rotation projects are available in any of our ongoing studies in all four cancers described above.

Lab Personnel:
Nicole Anderson (Postdoctoral Fellow)
Michele Burrows (Lab Manager)
Madeleine Carens (Research Specialist)
Nathan Coffey (M.D. / Ph.D. Student)
Xu Han (Ph.D. Student)
Christine Jiang (Ph.D. Student)
Brian Keith (Adjunct Professor)
Laura Kim (Postdoctoral Fellow)
Nicholas Lesner (Postdoctoral Fellow)
Graham Lobel (M.D. / Ph.D. Student)
Bailey Nance (Ph.D. Student)
Carson Poltorack (M.D./ Ph.D. Student)
Roman Riscal (Postdoctoral Fellow)
Nicolas Skuli (Senior Research Investigator)
Sreyans Tanga (Undergraduate Researcher)

Selected Publications

Riscal, R., C. J. Bull, C. Mesaros, J. M. Finan, M. Carens, E. Ho, J. Xu, J. Godfrey, P. Brennan, M. Johansson, M. P. Purdue, S. J. Chanock, D. Mariosa, N. J. Timpson, E. V. Vincent, B. Keith, I. A. Blair, N. Skuli, and M. C. Simon: Cholesterol auxotrophy as a targetable vulnerability in clear cell renal cell carcinoma. Cancer Discovery 2021 Notes: Highlighted in Nature Reviews Urology, DoD Kidney Cancer Research Program, CURE, Penn News Today, and ACC Bulletin.

Devalaraja, S., T. K. J. To, I. W. Folkert, R. Natesan, Md. Z. Alam, M. Li, Y. Tada, K. Budagyan, M. Dang, L. Zhai, G. P. Lobel, G. E. Ciotti, T. S. K. Eisinger-Mathason, I. A. Asangani, K. Weber, M. C. Simon, and M. Haldar : Tumor-derived retinoic acid regulates intratumoral monocyte differentiation to promote immune suppression and resistance to immune checkpoint blockade. Cell 180: 1098-1114, March 2020 Notes: Higlighted in Cancery Discovery, Semantic Scholar, New England Journal of Medicine, the USDA.

P. Lee, D. Malik, N. Perkons, P. Huangyang, S. Kaare, S. Rhoades, Y.Y. Gong, M. Spata, J.M. Finan, I. Nissim, T.P.F. Gade, A.M. Weljie, M.C. Simon: Targeting glutamine metabolism slows soft tissue sarcoma progression. Nature Comm. 11: 498, January 2020.

Fuming, L., P. Huangyang, M. Spata, K. Guo, R. Riscal, J. Godfrey, K.E. Lee, N. Lin, P. Lee, I.A. Blair, B. Li, B. Keith, and M.C. Simon: FBP1 loss disrupts liver metabolism and promotes tumourigenesis via a hepatic stellate cell senescence secretome. Nature Cell Biol. 22(6): 728-739, May 2020 Notes: Highlighted in Cancer Discovery, Life Sciences Network, ACC Bulletin, and Technology Networks.

P. Huangyang, F. Li, P. Lee, I. Nissum, A.M. Weljie, A. Mancuso, B. Li, B. Keith, S. Yoon, and M.C. Simon: FBP2 inhibits sarcoma progression by restraining mitochondrial biogenesis. Cell Metabolism. Cell Metabolism 31: 174-188, January 2020 Notes: Highlighted by Life Sciences Network.

Lin, N., J. E. S. Shay, H. Xie, D. S. M. Lee, N. Skuli, Q. Tang, Z. Zhou, A. Azzam, H. Meng, H. Wang, G. A. FitzGerald, and M. C. Simon: Myeloid cell hypoxia-inducible factors promote resolution of inflammation. Front. Immunology 9: 1-21, November 2018.

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 27(6): 1263-1280, June 2018 Notes: Highlighted in Nature Reviews Urology.

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.

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.

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 Signaling, and the NCI website; "Breakthrough of the Year" NRU.

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Last updated: 09/23/2021
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