Intersection of cytoskeletal regulation with tumor cell metabolism

SUMMARY Pancreatic cancer (PDAC) is particularly lethal, due in part to a resistance to therapies and a high incidence of metastasis. The overall goal of our research program is to define the molecular mechanisms regulating tumor progression and metastasis of PDAC, thereby identifying new therapeutic strategies to improve patient survival. This proposal focuses on an activator of the invasive cytoskeletal machinery, the proto-oncogene Vav1, which is a GTP exchange factor and activator of the potent Rac/Cdc42 small GTPases that regulate actin dynamics. Vav1 is aberrantly expressed in a subset of pancreatic tumors and correlates with a poor prognosis. Here we have identified a novel role for Vav1 in the regulation of glutamine metabolism that we believe contributes to cellular energy levels, thereby integrating a potent pro-invasive factor with an essential metabolic axis in PDAC. Vav1 promotes the conversion of glutamine to glutamate via the enzyme glutaminase (GLS1). Further, we have identified novel mechanisms by which the glutamine/glutamate axis contributes to tumor progression and metastasis through both localized energy production and through paracrine signaling by both glutamate and inflammatory cytokines. Our substantial preliminary data support the hypothesis for this proposal that ectopic expression of the Rac/Cdc42 exchange factor Vav1 regulates glutamine metabolism to link nutrient status to actin dynamics, invasion, and proliferation. Using a combination of cell biology, live cell fluorescence microscopy, biochemistry, and in vivo models, we will test this hypothesis by investigating how Vav1 amplifies glutamine catabolism (Aim 1), and how glutamate production drives tumor progression and metastasis in pancreatic tumor cells (Aim 2). Successful completion of this research will provide fundamental mechanistic advances in our understanding of the metabolic dependencies of PDAC, identify therapeutic vulnerabilities for patients with Vav1- positive tumors, and establish novel links between cytoskeletal signaling and glutamine metabolism.