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. Critical responses to this stress 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.

We focus on the following human cancers: kidney cancer, liver cancer, pancreatic cancer and soft tissue sarcoma. Patient derived samples obtained from individuals afflicted with these cancers are evaluated via multi-omic approaches (bulk RNAseq, single cell RNAseq, spatial transcriptomics, proteomics, and metabolomics) to develop hypotheses tested via short term genetically engineered mouse models, patient derived organoids, and patient derived xenografts via an integrated ‘omics assessment of "tumor neighborhoods” within the tumor microenvironment. We are particularly interested in how changes in malignant cell metabolism allow pancreatic and liver cancer cells to "out-compete" for critical nutrients like arginine, glutamine and lipids that influence cytotoxic T cell and myeloid cell activity. Of particular interest are metabolic “symbioses” between tumor cells and other cells in the microenvironment, as well as metabolic “synapses" that allow cancer cells experiencing extreme hypoxia and nutrient deprivation survive in intrinsically stressful microenvironments that are particularly relevant to pancreatic cancer. We are also very interested in the interplay between various stromal components that include cancer associated fibroblasts and immune cells that promote primary tumor growth and metastatic dissemination.

By studying patient tumors via integrated ‘omics, we have identified attractive therapeutic targets. For example, the HIF2 inhibitor Belzutifan is now FDA approved for kidney cancer while other targets we have identified are currently undergoing development for clinical trials. Stress responses (HIF, ER stress, autophagy, mTOR signaling, etc.) that help cancer cells and recruited immune cells avoid programmed cell death mediated by either apoptosis or ferroptosis are also under evaluation. While drugs that impact apoptosis are in widespread clinical use, ferroptosis targeted drugs are in their therapeutic infancy and require further study and an exciting new focus of the lab.


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 that includes spatial transcriptomics, proteomics, and metabolomics, 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:
Morgan Brown (PhD Student)
Pamela Burgess-Jones (Lab Manager)
Xuanyan Cai (Postdoctoral Fellow)
Sara Demczyszyn (Research Specialist)
Xu Han (Postdoctoral Fellow)
Christina Jackson (Assistant Professor, Neurosurgery)
Christine Jiang (Ph.D. Student)
Brian Keith (Adjunct Professor)
Laura Kim (Postdoctoral Fellow)
Nicholas Lesner (Postdoctoral Fellow)
Yi Ning (Postdoctoral Fellow)
Bailey Nance (Ph.D. Student)
Carson Poltorack (M.D./ Ph.D. Student)
Yizheng Xue (Visiting Student)
Nicolas Skuli (Senior Research Investigator)
Emily Zhang (Undergraduate Researcher)
Denise Zheng (Undergraduate Researcher)

Selected Publications

Alexander, K.A., Y. Ruofan, N. Skuli, N.J. Coffey, S. Nguyen, C. Faunce, H. Huang, I.P. Dardani, A.L. Good, J. Lim, C. Li, N. Biddle, E.F. Joyce, A. Raj, D. Lee, B. Keith, M.C. Simon, S. Berger : Nuclear speckles regulate HIF-2α programs and correlate with patient survival in kidney cancer. Nature Cell Biology, in press 2024.

Li, F., W. Mi, L. Li, M. Burrows, J. Plesset, A. Majer, J. Li, B. Keith, and M. C. Simon : Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 1 inhibition in liver cancer. Nature Cancer 5:131-146 January 2024.

Missiaen R., N. M. Anderson, L. C. Kim, B. Nance, M. Burrows, N. Skuli, M. Carens, R. Riscal, A. Steenels, F. Li, X. Han, and M. C. Simon: GCN2 inhibition sensitizes arginine deprived hepatocellular carcinoma cells to sentolytic treatment. Cell Metab 34: 1151-1167, August 2022 Notes: Highlighted in Cancer Discovery, EMBO J., Genetic Engineering News, Inside Precision Medicine, J. National Comprehensive Cancer Center Network.

Riscal, R., C. J. Bull, C. Mesaros, J. M. Finan, M. Carens, E. S. Ho, J. P. 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 11: 3106-3125, December 2021 Notes: Highlighted in Nature Reviews Urology, DoD Kidney Cancer Research Program, CURE, Penn News Today, and ACC Bulletin.

Huangyang, P., 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.

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.

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.

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.

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: 08/06/2024
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