Research

Scientific Research

Alterations in the metabolism of cancer cells is a defining 'hallmark of cancer'. Historically, therapies that selectively inhibit the altered metabolism of cancer cells have shown great success in the clinic. However, it remains largely unclear how many recurrent features of cancer metabolism contribute to cancer cell growth, survival, and therapeutic resistance. Throughout my academic training, I sought to better understand the links between cancer-associated genes, metabolism, and cell death in cancer to improve patient outcomes. 

Postdoctoral Research

NCI/NIH K00 Postdoctoral Fellow

Laboratory of Ralph DeBerardinis

Howard Hughes Medical Institute

UT Southwestern Medical Center, Dallas, TX

April 2020- February 2023


The role of nitrogen metabolism in renal cell carcinoma

Addiction to glutamine consumption is a known hallmark of renal cell carcinoma. Therapies that disrupt glutamine catabolism through inhibition of glutaminase (GLS) or glutamine amidotransferases have shown promise in preclinical studies. However, a recent clinical trial of the GLS inhibitor CB-839 failed to reach its target endpoint in phase II trials in patients with metastatic ccRCC. A possible explanation for the failure of GLS inhibitors in the clinic is that our current understanding of the mechanisms of glutamine catabolism in vivo are incomplete. To address this question, I used patient-derived tumor xenografts to trace the metabolic fate of glutamine in vivo. Using a stable isotope of glutamine labeled at both its carbons and nitrogens and high resolution LC/MS, I investigated the metabolic routes and kinetics of glutamine nitrogen and carbon metabolism in vivo. This work uncovered an unexpected role for the transaminase enzymes in rapidly shuttling glutamine-derived nitrogens in both cancer cells and in healthy mouse tissues. 


Publications

Doctoral Research

NSF GRFP Predoctoral Fellow

NCI/NIH K99 Predoctoral Fellow

Laboratory of Scott Dixon

Stanford University, Stanford, CA

August 2014- April 2020


The role of the p53-p21 pathway in metabolic stress-induced ferroptosis

Ferroptosis is an oxidative, iron-dependent form of non-apoptotic cell death that occurs due to the lethal accumulation of toxic lipid reactive oxygen species (ROS). Ferroptosis can be induced by deprivation of the amino acid cysteine and is suppressed by the endogenous antioxidant glutathione. p53 is a master regulator of cell death and survival that plays a critical role in suppressing cancer initiation and progression. I found that chronic activation of p53 using the small molecule nutlin-3 profoundly suppressed ferroptosis induced by cysteine deprivation. p53 activation promoted the transcription of CDKN1A (encoding p21) leading to cell cycle arrest and cell survival. I further found that activation of the p53-p21 pathway led to the suppression of the glutathione-dependent enzyme ribonucleotide reductase (RNR), thus conserving glutathione and redirecting it towards antioxidant defense. This work provided further evidence of the critical role of p53 as a regulator of metabolic stress and non-apoptotic cell death. Furthermore, these experiments identified a novel mechanism by which cell cycle arrest and RNR inhibition can reroute glutathione to promote cell survival during metabolic stress. 


Publications

Post-Bacchalaureate Research

Research Technician II

Laboratory of Patrick Viatour

Children's Hospital of Philadelphia, Philadelphia, PA

July 2012 - August 2014

Amplification of E2F transcriptional activity in Rb-family deficient hepatocellular carcinoma drives tumor progression and metabolic reprogramming

The Rb-family of tumor suppressors (Rb, p107, p130) are functionally inactivated in the majority of human hepatocellular carcinomas. Rb-family loss leads to the enhanced transcription of numerous genes implicated in tumor initiation and progression. In the absence of the Rb-family, the activity of the E2F1 transcription factor becomes progressively amplified. E2F1 accumulation allows for the recruitment of a chromatin-remodeling complex that enhances chromatin accessibility. Subsequent remodeling of the chromatin landscape enhances the transcriptional output of key genes that drive cancer progression. These target genes include many metabolic enzymes implicated in glycolytic metabolism. This work defines a transcriptional and epigenetic mechanism by which Rb-family loss leads to the progressive acquisition of oncogenic phenotypes, such as the Warburg Effect.


Publications


Pre-Bacchalaureate Research

Undergraduate Research Assistant

Laboratory of Paula Oliver

Children's Hospital of Philadelphia, Philadelphia, PA

March 2010 - August 2012


The role of the gut microbiota in T cell activation and inflammatory disease of mice lacking E3 ubiquitin ligase adaptor protein Ndfip1

The bacteria inhabiting the mammalian gastrointestinal (GI) tract play a vital role in normal digestion and immune function. In a healthy host, the immune system is tolerant to gut bacteria and does not mount an effector response to bacteria-derived antigens. Loss of tolerance to intestinal microflora has been associated with inflammatory bowel disease (IBD) in both mice and humans. Mice lacking Ndfip1, an adaptor protein for E3 ubiquitin ligases of the Nedd4-family, in T cells (Ndfip1-cKO) develop a disease resembling IBD. Inflammation in these mice is characterized by increased activation of peripheral T cells, infiltration of eosinophils into the GI tract, and epithelial hypertrophy in the esophagus. We hypothesized that this intestinal inflammation in Ndfip1-cKO mice is caused by a loss of T-cell tolerance to bacterial antigens. We showed that treatment of Ndfip1-cKO mice with broad-spectrum antibiotics drastically reduced bacterial load in stool but had little effect on T-cell activation and did not affect eosinophil infiltration into the GI tract or epithelial hypertrophy in the esophagus. Thus, inflammation in Ndfip1-cKO mice is not caused by a loss of tolerance to intestinal microbiota. Rather, T cell activation and eosinophilia may instead be triggered by other environmental antigens.

Publications

Kurzweil V*, Tarangelo A*, Oliver PM. (2012). Gastrointestinal microbiota do not significantly contribute to T cell activation or GI inflammation in Ndfip1-cKO mice. PLoS One, 7(4). e34478. *Co-first authors [Full Text]