Caitlyn Brashears
Program: Molecular Cell Biology
Current advisor: Brian Van Tine, MD, PhD
Undergraduate university: Baylor University
Research summary
Alterations in redox balance and redox signaling are known hallmarks of tumor metabolism. Cancer cells exhibit an increased reactive oxygen species (ROS) burden relative to normal tissues. The distinct mechanisms underlying altered redox balance are diverse and can broadly result from enhanced production of ROS and/or reduced ROS scavenging capacity in cancer cells. While specific reactive oxygen species can contribute to tumorigenesis and serve as essential signaling molecules, overabundance of ROS can result in lethal, oxidative damage to DNA, protein, and lipids. As a result, the maintenance of elevated ROS levels within tumor cells is precarious and tightly regulated. The unique redox metabolism of cancer cells, therefore, has become a promising therapeutic target in the field of tumor metabolism. My research primarily focuses on investigating the unique redox metabolism of sarcoma for the development of targeted therapeutics. Through unbiased screening of mRNA expression in multiple sarcoma subtypes we identified unique gene expression patterns in synovial sarcoma and osteosarcoma that result in aberrations to redox metabolism.
Specifically synovial sarcoma is the first cancer identified that uniformly lacks expression of Malic Enzyme 1 (ME1). ME1 catalyzes the oxidative decarboxylation of malate to pyruvate, producing NADPH in the process. NADPH is an essential reducing equivalent within the cell, providing electrons for reductive biosynthesis and the recycling of cellular antioxidant systems. Absence of ME1 results in broad changes to cellular redox metabolism including enhanced reliance upon the oxidative pentose phosphate pathway to produce NADPH and dependence upon the thioredoxin antioxidant system for ROS scavenging. Additionally, cells that lack ME1 expression exhibit an increased ROS burden are sensitized to the induction of ferroptosis both in vitro and in vivo.
PHGDH overexpression in osteosarcoma patient samples is a recurrent metabolic feature that correlates with significantly worse patient prognosis. PHGDH is the rate limiting enzyme in the de novo serine synthesis pathway, which has been linked to mitochondrial NADPH production and redox homeostasis in cancers and endothelial tissues. Unbiased screening of whole metabolomic data revealed significant reductions in GSH/GSSG ratios upon inhibition of PHGDH in osteosarcoma cell lines. Characterization of ROS levels in osteosarcoma cell lines treated with NCT-503, a small molecular inhibitor of PHGDH, revealed significant accumulation of mitochondrial ROS. Collectively, these data suggest that de novo serine synthesis is necessary for redox homeostasis in osteosarcoma. Inhibition of PHGDH resulted in significantly increased expression of SLC7A11, the cystine-glutamate antiporter of system xCT. Consistently, treatment with PHGDH induced increased cystine import in osteosarcoma and increased xCT plasma membrane expression. We hypothesized that PHGDH inhibition increased dependency upon exogenous cystine import through xCT. Consistent with this hypothesis, treatment with NCT-503 significantly increased sensitivity to xCT inhibition in vitro resulting in significant cell death in physiologic conditions. Taken together these research aims highlight a powerful approach for the development of targeted therapeutics based on redox metabolism in sarcoma
Graduate publications
Brashears CB, Prudner BC, Rathore R, Caldwell KE, Dehner CA, Buchanan JL, Lange SES, Poulin N, Sehn JK, Roszik J, Spitzer D, Jones KB, O’Keefe R, Nielsen TO, Taylor EB, Held JM, Hawkins W, Van Tine BA. 2022 Malic Enzyme 1 Absence in Synovial Sarcoma Shifts Antioxidant System Dependence and Increases Sensitivity to Ferroptosis Induction with ACXT-3102. Clin Cancer Res, 28(16):3573-3589.
Rathore R, Caldwell KE, Schutt C, Brashears CB, Prudner BC, Ehrhardt WR, Leung CH, Lin H, Daw NC, Beird HC, Giles A, Wang WL, Lazar AJ, Chrisinger JSA, Livingston JA, Van Tine BA. 2021 Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma. Cell Rep, 34(4):108678.
Brashears CB, Barlin M, Ehrhardt WR, Rathore R, Schultze M, Tzeng SC, Van Tine BA, Held JM. 2020 Systems level profiling of arginine starvation reveals MYC and ERK adaptive metabolic reprogramming. Cell Death Dis, 11(8):662.
Kremer JC, Prudner BC, Lange SE, Bean GR, Schultze MB, Brashears CB, Radyk MD, Redlich N, Tzeng SC, Kami K, Shelton L, Li A, Morgan Z, Bomalaski JS, Tsukamoto T, McConathy J, Michel LS, Held JM, Van Tine BA. 2017 Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers. Cell Rep, 18(4):991-1004.