Glutaminolysis: A Hallmark of Cancer Metabolism
Doctor of Philosophy
The goals of these projects are to study the critical role of glutamine (Gln) in ovarian cancer growth, metastasis, drug resistance and sources of glutamine in tumor microenvironment. 1): Gln‐addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. 1): we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low‐invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high‐invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high‐invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low‐invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs. 2): Reactive stromal cells are an integral part of tumor microenvironment (TME) in tumors and interact with cancer cells to regulate their growth and survival. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets which make cancer cells vulnerable has remained challenging and still elusive. Here, we identify a previously unrecognized mechanism whereby metabolism of reactive stromal cells is reprogrammed through upregulated glutamine anabolic pathway. This dysfunctional stromal metabolism confers atypical metabolic flexibility and adaptive mechanisms in stromal cells allowing them to harness carbon and nitrogen from noncanonical sources to synthesize glutamine in nutrient-deprived conditions existing in TME. We demonstrate that targeting cancer associated fibroblasts (CAFs), a major component of reactive stroma that expresses high glutamine synthetase (GLUL), disrupts metabolic crosstalk between stromal and cancer cells. Our work underscores reliance of cancer cells on CAFs and presents a synthetic lethal approach to target tumor stroma and cancer cells simultaneously for desirable therapeutic outcomes.