The laboratory of Ji Zhang, PhD, uses biochemical, cellular and molecular biology and mouse genetic approaches to understand the fundamental mechanisms that underlie tumor cells' response to various metabolic stresses.
The Zhang Lab is located within the Hematologic Malignancies and Stem Cell Biology research group at the Herman B Wells Center for Pediatric Research.
Three major research projects in Dr. Zhang's lab are:
1. Understand the mechanism of resistance
to L-asparaginase treatment in pediatric acute lymphoblastic leukemia (ALL).
L- asparaginase is used to treat pediatric ALL patients. However, resistance can occur to compromise the therapeutic efficacy. The Zhang Lab is using cell culture, mouse ALL models and patient samples to understand the molecular mechanism that drives resistance to L-asparaginase treatment with the goal of identifying new therapeutic targets to enhance the efficacy of L- asparaginase.
2. Elucidate the interplay between oncogenic signaling and nutrient acquisition/utilization in lymphoid malignancies.
It is well-accepted that oncogenic signaling reprograms tumor cell metabolism to support growth and survival under nutrient limiting environment. However, whether nutrient availability can modulate oncogenic signaling as a means of metabolic adaptation has not been extensively explored. Using B cell lymphoma as a model, the Zhang Lab will explore the molecular connections as well as potential therapeutic implication.
3. Explore the role of nonessential amino acid metabolism in normal hematopoiesis.
Hematopoiesis in adult originates from bone marrow where nutrient and oxygen are thought to be limited. As a result, understanding the metabolic regulation of normal hematopoiesis has become an emerging topic recently. Using mouse genetic models with deficiency on specific metabolic pathways the Zhang lab will investigate the role of nonessential amino acid metabolism in hematopoietic stem cell maintenance and differentiation.
Halbrook CJ, Thurston G, McCarthy A, Nelson BS, Sajjakulnukit P, Krall AS, Mullen PJ, Zhang L, Batra S, Viale A, Stanger BZ, Christofk HR, Zhang J, di Magliano MP, Jorgensen C, Lyssiotis CA. Clonal Heterogeneity Supports Mitochondrial Metabolism in Pancreatic Cancer. Nature Cancer. 2022; 3(11): 1386-1403.
Ramdas B, Palam L, Singh-Mali R, Pasupuleti SK, Zhang J, KelleyM, Paczesny S, Zhang C, Kapur R. Combined heterozygosity of FLT3ITD TET2 and DNMT3A results in aggressive leukemia in mice and humans utilizing similar genetic programs. Journal of Clinical Investigation Insight. 2022; 7(18): e162016. doi:10.1172/jci.insight.162016.
Srivastava S, Jiang J, Misra J, Seim G, Staschke KA, Zhong M,Zhou L, Liu Y, Chen C, Davé U, Kapur R, Batra S, Zhang C, ZhouJ, Fan J, Wek RC, Zhang J. Asparagine bioavailability regulates the translation of MYC oncogene. Oncogene. 2022; 41(44): 4855-4865.
Ramdas B, Yuen LD, Palam L, Patel R, Pasupuleti SK, Jideonwo V, Zhang J, Maguire C, Wong E, Zhang C, Sandusky G, ChanRebecca, Zhang C, Stieglitz E, Haneline L, Kapur R. Inhibition of BTK and PI3Kδ impairs the development of Human JMML Stem and Progenitor cells. Molecular Therapy. 2022; 30(7): 2505-2521.
Jiang J, Batra S, Zhang J. Asparagine, a key metabolite to be targeted in cancers. Metabolites. 2021; 11(6): 402.
Jiang J, Srivastava S, Seim G, Pavlova NN, King B, Zou L, Zhang C, Zhong M, Feng H, Kapur R, Wek RC, Fan J, Zhang J. Promoter demethylation of the asparagine synthetase gene is required for an ATF4-dependent adaptation to asparagine depletion. Journal of Biological Chemistry. 2019; 294(49):18674-18684
Jiang J, Srivastava S, Zhang J. (Review) Starve Cancer Cells of Glutamine: Break the Spell or Make a Hungry Monster? Cancers. 2019 Jun 11;11(6). pii: E804. doi: 10.3390/cancers11060804
As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Hui S, Ghergurovich JM, Fan J, Intlekofer AI,White RM, Rabinowitz JD, Thompson CB§ , Zhang J§ (§ co-corresponding author). Cell Metabolism. 2018; 27 (2): 428-438. PMCID: PMC5803449
Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. Zhang J, Pavlova NN, Thompson CB. The EMBO journal. 2017; 36(10):1302-1315. PMID: 28420743
Rodney Claude, PhD student
Sankalp Srivastava, PhD student
Minghua Zhong, Research Technician
