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Reprogramming Metabolic Networks in the Tumor Microenvironment

肿瘤微环境中的代谢网络重编程

基本信息

批准号：
10305402
负责人：
Samuel Andrew Kerk
金额：
$ 4.55万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305402
关键词：
Ablation Affect Amino Acids Animals Architecture Aspartate Biochemical Pathway Bioenergetics CRISPR library Cancer Biology Cell physiology Cells Chemicals Clinical Trials Coculture Techniques Communication Complex Coupled Data Deoxycytidine Desmoplastic Disease Doctor of Philosophy Effector Cell Equilibrium Fellowship Fibroblasts GOT2 gene Genes Genetic Genetic Screening Genome Glutamates Goals Growth Immune Immune system Immunocompetent Immunotherapy Impairment Infiltration Investigation Isotopes Knock-out Knowledge Libraries Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mentorship Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Mus Myelogenous Nature Nerve Nervous system structure Neurons Neurotransmitters Nutrient Oxaloacetates Oxidation-Reduction Oxygen Pancreatic Ductal Adenocarcinoma Peripheral Nerves Phase Physiological Population Postdoctoral Fellow Production Pyrimidine Pyrimidines Pyruvate Regulatory T-Lymphocyte Research Personnel Resistance Role Schools Signal Transduction Support System Supporting Cell T-Lymphocyte Technical Expertise Techniques Testing Therapeutic Tissues Training Transaminases Treatment Efficacy Tumor-Infiltrating Lymphocytes Tumor-associated macrophages Vertebral column Work amino acid metabolism anti-tumor immune response base blood vessel development cancer cell career career development chemotherapy conditional knockout cytotoxic cytotoxicity gemcitabine in vivo in vivo Model inhibitor/antagonist macrophage metabolic abnormality assessment metabolomics mitochondrial metabolism mouse model neural network neurotransmission novel therapeutics nucleobase pancreatic cancer cells pancreatic cancer model pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm recruit relating to nervous system response targeted treatment therapy resistant tumor tumor ablation tumor growth tumor metabolism tumor microenvironment tumorigenesis tumorigenic

项目摘要

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.

项目总结