Reprogramming Metabolic Networks in the Tumor Microenvironment

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PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a deadly disease and better therapies are urgently needed. The pancreatic tumor microenvironment is complex, and stromal and immune cells induce an inflamed, desmoplastic response that hinders proper blood vessel formation, resulting in poor nutrient and oxygen delivery. Therefore, PDA cells must rewire cellular metabolism to maintain their biosynthetic and energetic requirements. The stromal and immune cells do not simply change tumor architecture, they also support cancer metabolism, suppress anti-tumor immune responses, and blunt treatment efficacy. Having previously identified a new pathway of metabolic crosstalk between cancer cells and cancer-associated fibroblasts (CAFs), I now propose to extend this paradigm to discover how the immune and nervous systems support tumor metabolism to identify new therapeutic opportunities. Tumor-associated macrophages (TAMs) comprise the bulk of the immune compartment in a pancreatic tumor and support malignant progression and therapeutic resistance. In accordance with this, our group previously demonstrated that TAMs release the pyrimidine deoxycytidine (dC), which, based on its molecular similarity, is able to inhibit the cytotoxic activity of the frontline chemotherapeutic gemcitabine. Since the amino acid aspartate (Asp) is required for pyrimidine production, and Asp is produced by the glutamate oxaloacetate transaminases (GOTs), I generated macrophage-specific Got1 or Got2 knockout models to study the role of the GOTs in TAM metabolism. In Aim 1a, I will evaluate how Asp synthesis and dC release in TAMs impacts PDA sensitivity to gemcitabine using syngeneic tumor models. My preliminary data also suggests that GOT activity and dC modulate T cell function. Therefore, in Aim 1b, I will determine how loss of Got1 or Got2 in TAMs affects tumor infiltrating T cells and tumor response to immune-based therapy. During the K00 phase, I will apply knowledge gained during graduate school in cancer biology and metabolism to an independent postdoctoral project. Pancreatic tumors are highly innervated and neural ablation impairs tumor regression. The metabolic underpinnings by which neurons support cancer cells require further investigation. Therefore, my goal as a postdoctoral fellow is to understand how dysregulated PDA metabolism impacts neuronal recruitment and function as well as metabolic pathways in neurons that are critical for pro- tumor signaling. I plan to use genetic mouse models of PDA, in vivo isotope tracing, genome CRISPR libraries, and ex vivo neuron-PDA co-culture models to answer these questions. Lastly, in addition to the proposed studies, this training plan includes activities important for career development, mentorship, networking, and scientific communication to prepare me for successful transition to a postdoctoral fellowship and my career as an independent investigator studying cancer metabolism.