M. Celeste Simon, Ph.D.
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
Miami University, 1977.
Ohio State University, 1980.
Ph.D. (Molecular Biology)
The Rockefeller University, 1985.
Description of Research ExpertiseResearch Interests
Our laboratory studies cancer cell metabolism, tumor immunology, metastasis, and cellular responses to oxygen deprivation.
Key words: hypoxia; cancer metabolism; immunology; metastasis; in vivo and ex vivo models of pancreatic; liver; 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, glutamine, 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 and glutamine. 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 of immune cells, such as B cells, T cells, macrophages, neutrophils, 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 and serine 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 has launched multi-site clinical trials using B cell inhibitors in conjunction with standard of care, such as gemcitabine and abraxane.
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 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.
Generation of genetically engineered mice, CRISPR-based gene editing, ex vivo 3D organotypic culture, TCGA data mining, bioinformatics, next generation sequencing, ChIP-Seq, epigenetics, proteomics, analysis of archived human tumor samples, 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. Whatever it takes!!
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.
Nicole Anderson (Postdoctoral Fellow),
Jennifer Finan (Research Specialist),
Jason Godfrey (Ph.D. Student),
Brian Keith (Adjunct Professor),
Sanika Khare (Ph.D. Student),
Pearl Lee (Postdoctoral Fellow),
Fuming Li (Postdoctoral Fellow),
Rindert Missiaen (Postdoctoral Fellow),
Amanda Moreno (Undergraduate Researcher)
Romain Riscal (Postdoctoral Fellow),
Danielle Sanchez (Ph.D. Student),
Nicolas Skuli (Senior Research Investigator),
Michele Spata (Research Specialist),
Hong Xie (Ph.D. Student),
Peiwei Huang Yang (Ph.D. Student).
Selected PublicationsLin, 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. Immun. 9: 1-21, November 2018.
Ackerman, D., S. Tumanov, B. Qiu, E. Michalopoulou, M. Spata, A. Azzam, H. Xie, M. C. Simon, and J. J. Kamphort: Triglycerides promote lipid homeostasis during hypoxic stress by balancing fatty acid saturation. Cell Reports 24(10): 2596-2605, September 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.
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-Mathason, 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.
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.