DALLAS – April 30, 2019 – Scientists at the Children’s Medical Center Research Institute at UT Southwestern (CRI) are using…
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.
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
Cancer 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
A 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 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 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. His laboratory is interested in the role of altered metabolic states in human diseases, particularly pediatric inborn errors of metabolism and cancer.
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. (2017). Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans. Cell Rep. 27, 1376-1386. (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)
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)
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)
Vander Heiden, M.G., and DeBerardinis, R.J. (2017). Understanding the intersections between metabolism and cancer biology. Cell 168, 657-699. (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)
Divya Bezwada, M.S.
Feng Cai, Ph.D.
Ling Cai, Ph.D.
Dennis Dumesnil, M.S.
Brandon Faubert, Ph.D.
Wen Gu, Ph.D.
Robert Harris, B.S.
Fang Huang, M.D., Ph.D.
Kendra Johnston, M.D.
Akash Kaushik, Ph.D.
Bookyung Ko, M.A., M.S.
Markey McNutt, M.D., Ph.D.
Min Ni, Ph.D.
Panayotis Pachnis, MBBS, Ph.D.
Chunxiao Pan, Ph.D.
Alan Poole, M.D., Ph.D.
Aparna Rao, MBBS, Ph.D.
Thomas Rogers, Ph.D.
Ashley Solmonson, Ph.D.
Jessica Sudderth, B.S.
Danny Vu, Ph.D.
Chendong Yang, M.D., Ph.D.
Lauren Zacharias, M.S.
Faith Zhang, M.D., Ph.D.
Lindsey Boroughs, Ph.D.
Postdoctoral Fellow (2013-2016)
Mary Calvaruso, Ph.D.
Visiting Fellow (2013-2014)
Tzuling Cheng, Ph.D.
Postdoctoral Fellow (2009-2012)
Pei-Hsuan Chen, Ph.D.
Ph.D. Student (2010-2015)
Daniel de los Santos
Undergraduate Green Fellow (2014)
Robert Egnatchik, Ph.D.
Postdoctoral Fellow (2014-2016)
Christopher Hensley, M.D., Ph.D.
M.D./Ph.D. Student (2011-2015)
Zeping Hu, Ph.D.
Assistant Professor (2012-2016)
Lei Jiang, Ph.D.
Assistant Instructor (2009-2017)
Jiyeon Kim, Ph.D.
Postdoctoral Fellow (2012-2018)
Undergraduate Green Fellow (2011)
Andrew Mullen, Ph.D.
Ph.D. Student (2008-2013)
Hien Nguyen, Ph.D.
Postdoctoral Fellow (2011-2012)
Kristell Oizel, Ph.D.
Visiting Postdoctoral Fellow (2016-2017)
Pavel Pichurin, M.D., Ph.D.
Postdoctoral Fellow (2009-2011)
Kartik Rajagopalan, M.D., Ph.D.
M.D./Ph.D. Student (2010-2014)
Xiaolei Shi, Ph.D.
Ph.D. Student and HHMI International Student
Ajla Wasti, M.D.
Clinical Fellow (2012-2014)
DALLAS – Nov. 14, 2018 – Dr. Ralph DeBerardinis – Professor at the Children’s Medical Center Research Institute at UT Southwestern…
The Cancer Prevention and Research Institute of Texas (CPRIT) has awarded more than $6.1 million to Children’s Medical Center Research Institute…