Research Focus

Proper control of metabolism is required for essentially every basic biological process. Altered metabolism at the cellular level contributes to several serious diseases including inborn errors of metabolism (the result of inherited genetic defects in metabolic enzymes that lead to chemical imbalances in children) and cancer. Our laboratory seeks to characterize these metabolic disorders, understand how they compromise tissue function, develop methods to monitor metabolism in vivo and design therapies to restore normal metabolism and improve health.

In cancer, we study how oncogenic control of metabolism supports tumor initiation and progression. In inborn errors of metabolism, we use metabolomics and genomics to identify new disease genes and deepen our understanding of metabolism’s role in human health. Our research is tightly integrated with clinical activities in medical genetics, oncology and radiology, providing seamless opportunities to examine the relevance of our findings in patients.

Research Projects

Discovery of New Metabolic Pathways and Liabilities in Cancer Cells

Methods to Analyze Tumor Metabolism in Vivo

Discovering and Understanding Pediatric Inborn Errors of Metabolism

Discovery of New Metabolic Pathways and Liabilities in Cancer Cells

DeBerardinis Laboratory Ralph DeBerardinis Laboratory cancer metabolism research metabolic research metabolic disordersCancer cells use reprogrammed metabolic pathways to grow and resist stress encountered in the tumor microenvironment. We believe that reprogrammed pathways facilitate malignant transformation and enable tumor progression. Identifying these pathways will allow us to better understand the biology of cancer and to uncover new therapeutic targets. Our lab uses metabolomics, metabolic flux analysis, cell biology and animal models of cancer to study how tumor cells generate energy, build macromolecules and maintain redox balance. We seek to identify the processes, both intrinsic and extrinsic to the cancer cell, that affect tumor metabolism and to discover context-specific metabolic vulnerabilities that might provide a basis for new treatments.

Our lab has found a metabolic pathway that prevents oxidative stress in anchorage-independent cells (see figure). We discovered that loss of anchorage enhances mitochondrial reactive oxygen species (ROS), which limit cell survival and growth. Cancer cells counteract mitochondrial ROS by inducing a metabolic pathway that transmits reducing equivalents as NADPH from the cytosol to the mitochondria. This pathway involves cytosolic reductive carboxylation of alpha-ketoglutarate (alpha-KG) by isocitrate dehydrogenase-1 (IDH1) using NADPH produced by the pentose phosphate pathway. The resulting isocitrate or citrate enters the mitochondria, and IDH2 decarboxylates it, which generates mitochondrial NADPH to mitigate ROS (Jiang et al., Nature 2016).

Methods to Analyze Tumor Metabolism in Vivo

cancer metabolism researchA major challenge in cancer research is understanding which metabolic pathways operate in live tumors growing in a native microenvironment. Our lab has established clinical protocols combining multiparametric, preoperative imaging with intraoperative infusions of isotope-labeled nutrients (e.g., 13C-glucose) to solve this problem. Our technique allows us to assess metabolic flux in living, human tumors in the lung, brain and other organs and compare fluxes between tumor and adjacent benign tissues. We are also able to correlate metabolic activity with gene expression and histological features. As a result, we have identified numerous metabolic activities that traditional studies confined to cultured cells could not have predicted. We have also adapted our imaging/13C infusion techniques to mouse models of cancer, which allows us to test hypotheses arising from work in human cancer.

Our overall goal is to identify the various fuels that bona fide human tumors consume in vivo and to understand the relative influences of the oncogenotype and stroma on tumor metabolism.

Early results of this work (Hensley et al., Cell 2016) discovered regions of biological heterogeneity have predictable patterns of metabolic heterogeneity. Lung tumors consume a variety of nutrients in vivo, including glucose and a number of alternative fuels such as lactate, fatty acids, and amino acids. Areas of low perfusion as reported by dynamic contrast enhanced MRI have the highest preference for glucose oxidation, and areas of higher perfusion more prominently use alternative fuels (see below). Isotope labeling of tumors and lungs infused with [U-13C]glucose found flux values for enzymes such as pyruvate dehydrogenase and pyruvate carboxylase (PDH and PC) were twice as active in the tumors.

inborn errors of metabolismDiscovering and Understanding Pediatric Inborn Errors of Metabolism

Inborn errors of metabolism (IEMs) are childhood diseases that mutations in metabolic enzymes and nutrient transporters cause. They manifest with acute states of metabolic imbalance and chronic dysfunction of the brain, liver, heart and other organ systems. Although individually rare, altogether IEMs number in the hundreds and account for a substantial fraction of admissions to pediatric hospitals. Importantly, many IEMs are treatable once the underlying defect is identified. Thus, every IEM provides an opportunity to learn something new about human metabolism and discover new treatments for sick children.

We established a seamless collaborative environment between the clinical Division of Pediatric Genetics and Metabolism at UT Southwestern and the Genetic and Metabolic Disease Program (GMDP) in the CRI. An IRB protocol allows us to recruit any patient from the clinics into a series of research studies designed to better understand existing IEMs and to use genomics and metabolomics to discover new IEMs. We use metabolic functional analyses in patient-derived cells and, in some cases, novel mouse models to assess the effect of potentially disease-causing mutations. To learn more about this program, please visit the GMDP.

About Dr. DeBerardinis

Ralph DeBerardinis, cancer metabolism research

Ralph DeBerardinis earned a B.S. in biology from St. Joseph’s University and M.D. and Ph.D. degrees from the University of Pennsylvania. Dr. DeBerardinis was the first trainee in the combined residency program in pediatrics and medical genetics at The Children’s Hospital of Philadelphia (CHOP) and received several awards for teaching and clinical care. He ultimately achieved board certification in pediatrics, medical genetics and clinical biochemical genetics.

Dr. DeBerardinis performed postdoctoral research in Craig Thompson’s laboratory in the Penn Cancer Center from 2004 to 2007. He joined the faculty of the University of Texas Southwestern Medical Center in 2008 and joined the Children’s Medical Center Research Institute at UT Southwestern (CRI) shortly after its founding in 2012. Dr. DeBerardinis serves as chief of Pediatric Genetics and Metabolism at UT Southwestern and director of the Genetic and Metabolic Disease Program in the CRI.

Dr. DeBerardinis received an Outstanding Investigator Award from the National Cancer Institute in 2017 and the Edith and Peter O’Donnell Award in Medicine from The Academy of Medicine, Engineering and Science of Texas (TAMEST) in 2019. He holds the Joel B. Steinberg, M.D. Chair in Pediatrics, and he is a Sowell Family Scholar in Medical Research and a Robert L. Moody Faculty Scholar. In 2020, he was elected to the National Academy of Medicine.

Selected Publications

Faubert, B., Solmonson, A., and DeBerardinis, R.J. (2020). Metabolic reprogramming and cancer progression. Science. 368, eaaw5473. (Full Text)

DeBerardinis, R.J.(2020). Tumor Microenvironment, Metabolism, and Immunotherapy. N Engl J Med.  382, 869-871. (PubMed)

Tasdogan, A., Faubert, B., Ramesh, V., Ubellacker, J.M., Shen, B., Solmonson, A., Murphy, M.M., Gu, Z., Gu, W., Martin, M., Kasitinon, S.Y., Vandergriff, T., Mathews, T.P., Zhao, Z., Schadendorf, D., DeBerardinis, R.J., and Morrison S,J. (2020). Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 577,115-120. (PubMed)

Chen, P.H., Cai, L., Huffman, K., Yang, C., Kim, J., Faubert, B., Boroughs, L., Ko, B., Sudderth, J., McMillan, E.A., Girard, L., Chen, D., Peyton, M., Shields, M.D., Yao, B., Shames, D.S., Kim, H.S., Timmons, B., Sekine, I., Britt, R., Weber, S., Byers, L.A., Heymach, J.V., Chen, J., White, M.A., Minna, J.D., Xiao, G., and DeBerardinis, R.J. (2019). Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells. Mol Cell.76, 838-851. (PubMed)

Ni, M., Solmonson, A., Pan, C., Yang, C., Li, D., Notzon, A., Cai, L., Guevara, G., Zacharias, L.G., Faubert, B., Vu, H.S., Jiang, L., Ko, B., Morales, N.M., Pei, J., Vale, G., Rakheja, D., Grishin, N.V., McDonald, J.G., Gotway, G.K., McNutt, M.C., Pascual, J.M., and DeBerardinis, R.J. (2019) Functional Assessment of Lipoyltransferase- Deficiency in Cells, Mice, and Humans. Cell Rep. 27, 1376-1386. (PubMed)

Courtney, K.D., Bezwada, D., Mashimo, T., Pichumani, K., Vemireddy,V., Funk, A.M., Wimberly, J., McNeil, S.S., Kapur, P., Lotan, Y., Margulis, V., Cadeddu, J.A., Pedrosa, I., DeBerardinis, R.J., Malloy, C.R., Bachoo, R.M., and Maher, E.A. (2018). Isotope Tracing of Human Clear Cell Renal Cell Carcinomas Demonstrates Suppressed Glucose Oxidation In Vivo. Cell Metab. 28, 793-800. (PubMed)

Huang, F., Ni, M., Chalishazar, M.D., Huffman, K.E., Kim, J., Cai, L., Shi, X., Cai, F., Zacharias, L.G., Ireland, A.S., Li, K., Gu, W., Kaushik, A.K., Liu, X., Gazdar, A.F., Oliver, T.G., Minna, J.D., Hu, Z., and DeBerardinis, R.J. (2018). Inosine Monophosphate Dehydrogenase Dependence in a Subset of Small Cell Lung Cancers. Cell Metab. 28, 369-382. (PubMed)

Shi, X., Tasdogan, A., Huang, F., Hu, Z., Morrison, S.J., and DeBerardinis, R.J. (2017). The abundance of metabolites related to protein methylation correlates with the metastatic capacity of human melanoma xenografts. Sci Adv. 3, eaao5268. (PubMed)

Cai, L., Li, Q., Du, Y., Yun, J., Xie, Y., DeBerardinis, R.J., and Xiao, G. (2017). Genomic regression analysis of coordinated expression. Nat Commun. 8, 2187. (PubMed)

Jiang, L., Boufersaoui, A., Yang, C., Ko, B., Rakheja, D., Guevara, G., Hu, Z., and DeBerardinis, R.J. (2017). Quantitative metabolic flux analysis reveals an unconventional pathway of fatty acid synthesis in cancer cells deficient for the mitochondrial citrate transport protein. Metab Eng. 43, 198-207. (PubMed)

Faubert, B., Li, K.Y., Cai, L., Hensley, C.T., Kim, J., Zacharias, L.G., Yang, C., Do, Q.N., Doucette, S., Burguete, D., Li, H., Huet, G., Yuan, Q., Wigal, T., Butt, Y., Ni, M., Torrealba, J., Oliver, D., Lenkinski, R.E., Malloy, C.R., Wachsmann, J.W, Young, J.D., Kernstine, K., and DeBerardinis, R.J. (2017) Lactate Metabolism in Human Lung Tumors. Cell 171, 358-371. (PubMed)

Kim, J., Hu, Z., Cai, L., Li, K., Choi, E., Faubert, B., Bezwada, D., Rodriguez-Canales, J., Villalobos, P., Lin, Y-F., Ni, M., Huffman, K.E., Girard, L., Byers, L.A., Unsal-Kacmaz, K., Peña, C.G., Heymach, J.V., Wauters, E., Vansteenkiste, J., Castrillon, D.H., Chen, B.P.C., Wistuba, I,, Lambrechts, D., Xu, J., Minna, J.D., and DeBerardinis, R.J. (2017). CPS1 maintains pyrimidine pools and DNA synthesis is KRAS/LKB1-mutant lung cancer cells.  Nature 546, 168-172. (PubMed)

Hensley, C.T., Faubert, B., Yuan, Q., Lev-Cohain, N., Jin, E., Kim, J., Jiang, L., Ko, B., Skelton, R., Loudat, L., et al. (2016). Metabolic heterogeneity in human lung tumors. Cell 164, 681–694. (PubMed)

Jiang, L., Shestov, A.A., Swain, P., Yang, C., Parker, S.J., Wang, Q.A., Terada, L.S., Adams, N.D., McCabe, M.T., Pietrak, B., et al. (2016). Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532, 255–258. (PubMed)


Lab News


Lab Members

Divya Bezwada, M.S.

Ph.D. Student, Ruth L. Kirschstein NRSA Predoctoral Fellow

Eliot Blatt, Ph.D.

Postdoctoral Fellow

Bailey Brooks, B.S.

Research Technician

Feng Cai, metabolomics facility

Feng Cai, Ph.D.

Senior Research Scientist

Maggie Cervantes, B.S.

M.D./Ph.D Student

Hongli Chen, Ph.D

Senior Research Associate

Walter Chen, M.D., Ph.D.

Clinical Fellow, Neonatal-Perinatal Medicine

Dennis Dumesnil, M.S.

Research Technician

Wen Gu, Ph.D.

Postdoctoral Fellow

Lea Abou Haidar, M.D.

Postdoctoral Fellow

Bookyung Ko, metabolomics facility

Bookyung Ko, M.A., M.S.

Senior Research Associate

Xiangyi Li, M.D., Ph.D.

Senior Research Associate

Roger Liang

M.D./Ph.D. Student

Phyllis McDaniel, BSN, BBA, RN

Senior Research Nurse Coordinator

Phong Nguyen, Ph.D.

Postdoctoral Fellow

Grant Nickles, B.S.

Lab Technical Assistant for CRI

Min Ni, Ph.D.

Associate Professor, Research

K. Celeste Oaxaca, M.S.

Research Assistant

Ashley Solmonson, Ph.D.

Ruth L. Kirschstein NRSA Fellow

Varun Sondhi, M.D., Ph.D.

Pulmonary and Critical Care Fellow

Jessica Sudderth, metabolomics facility

Jessica Sudderth, B.S.

Lab Manager/Research Scientist

Trevor Tippetts, Ph.D.

Postdoctoral Fellow

Danny Vu, metabolomics facility

Danny Vu, Ph.D.

Senior Research Scientist

Zheng Wu, Ph.D.

Postdoctoral Fellow

Chendong Yang, M.D., Ph.D.

Research Scientist

Lauren Zacharias, metabolomics facility

Lauren Zacharias, M.S.

Research Associate

Lindsey Boroughs, Ph.D.

Field Medical Scientist, Bristol-Myers-Squibb

Postdoctoral Fellow (2013-2016)

Ling Cai, Ph.D.

Assistant Professor, Quantitative Biomedical Research Center, UT Southwestern

Postdoctoral Fellow (2014-2016)

Mary Calvaruso, Ph.D.

Instructor, Department of Biotechnology and Biology, Biccocca University

Visiting Fellow (2013-2014)

Tzuling Cheng, Ph.D.

Senior Scientist, IDEAYA Biosciences

Postdoctoral Fellow (2009-2012)

Pei-Hsuan Chen, Ph.D.

Scientist, Vertex Pharmaceuticals

Ph.D. Student (2010-2015)

Daniel de los Santos

Medical Student, University of Vermont

Undergraduate Green Fellow (2014)

Robert Egnatchik, Ph.D.

Senior Research and Development Engineer, PepsiCo

Postdoctoral Fellow (2014-2016)

Brandon Faubert, Ph.D.

Assistant Professor, Department of Medicine, University of Chicago

Canadian Institutes of Health Research Fellow (2015-2021)

Rob Harris, Ph.D.

MSTP Student, UT Southwestern Medical School

M.D./Ph.D Student (2016-2021)

Christopher Hensley, M.D., Ph.D.

Radiology Resident, University of Pennsylvania

M.D./Ph.D. Student (2011-2015)

Zeping Hu, Ph.D.

Assistant Professor, Tsinghua University

Assistant Professor (2012-2016)

Fang Huang, M.D., Ph.D.

Senior Visiting Scholar

Lei Jiang, Ph.D.

Assistant Professor, City of Hope

Assistant Instructor (2009-2017)

Akash Kaushik, Ph.D.

Senior Scientist, Internal Medicine Research Unit, Pfizer

Postdoctoral Fellow (2016-2022)

Sherwin Kelekar, Ph.D.

MSTP Student, UT Southwestern Medical School

M.D./Ph.D Student (2016-2022)

Jiyeon Kim, Ph.D.

Assistant Professor, University of Illinois at Chicago

Postdoctoral Fellow (2012-2018)

Sabin Kshattry

M.D./Ph.D. Student, UT Medical Branch

Undergraduate Green Fellow (2011)

Andrew Mullen, Ph.D.

Director of Operations, General Metabolics, LLC

Ph.D. Student (2008-2013)

Hien Nguyen, Ph.D.

Staff Scientist, University of Massachusetts Medical School

Postdoctoral Fellow (2011-2012)

Kristell Oizel, Ph.D.

Postdoctoral Fellow, Health Research Institute of the University of Nantes

Visiting Postdoctoral Fellow (2016-2017)

Panayotis Pachnis, MBBS, Ph.D.

Pediatrics Residency, UT Southwestern

Postdoctoral Fellow (2018-2021)

Pavel Pichurin, M.D., Ph.D.

Medical Geneticist, Mayo Clinic

Postdoctoral Fellow (2009-2011)

Alan Poole, M.D., Ph.D.

Assistant Professor, Pediatric Critical Care, UT Southwestern

Clinical Fellow (2016-2020)

Kartik Rajagopalan, M.D., Ph.D.

Pulmonary Critical Care Fellow, Columbia University Medical Center

M.D./Ph.D. Student (2010-2014)

Aparna Rao, MBBS, Ph.D.

Postdoctoral Scientist and Medical Oncologist, Peter MacCallum Cancer Centre

Postdoctoral Fellow (2018-2021)

Thomas Rogers, Ph.D.

Staff Scientist, Van Andel Institute

NCI Postdoctoral Fellow (2017-2022)

Tracy Rosales, Ph.D.

Field Application Scientist, ChemoMetec

Ph.D. Student, CPRIT Predoctoral Trainee (2017-2022)

Xiaolei Shi, Ph.D.

Physician-Scientist Training Program, Internal Medicine Residency, University of Minnesota

Ph.D. Student and HHMI International Student

Ajla Wasti, M.D.

Pediatric Oncologist, Shaukat Khanum Memorial Cancer Hospital

Clinical Fellow (2012-2014)

Faith Zhang, M.D., Ph.D

Assistant Professor, Radiation Oncology, UT Southwestern Medical Center

Clinical Fellow (2018-2023)

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