Investigating the metabolic regulation of tumor desmoplasia

研究肿瘤结缔组织形成的代谢调节

• 批准号: 10745369
• 负责人: Simon Schwörer
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-08 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745369
• 关键词: Acceleration; Advisory Committees; Affect; Amino Acids; Anabolism; Award; Bioenergetics; Biology; Cancer Model; Cancer Patient; Carbon; Citric Acid Cycle; Collaborations; Collagen; Communication; Data; Deposition; Desmoplastic; Development; Development Plans; Educational process of instructing; Environment; Extracellular Matrix; Extracellular Matrix Proteins; Face; Faculty; Fibroblasts; Future; Glutamate Dehydrogenase; Glutamates; Glutamine; Goals; Grant; Hyperactivity; Impairment; Investigation; Knowledge; Laboratories; Laboratory Research; Malignant Neoplasms; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metabolic; Metabolism; Mitochondria; Normal tissue morphology; Nutrient; Outcome; Oxidation-Reduction; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Phase; Positioning Attribute; Production; Prognosis; Proline; Proteins; Pyruvate; Pyruvate Carboxylase; Pyruvate Metabolism Pathway; Regulation; Reporting; Research; Research Personnel; Research Training; Resistance; Role; Solid; Solid Neoplasm; Therapeutic; Tissues; Transfer RNA Aminoacylation; Translations; Tumor Promotion; Vascular blood supply; Vertebral column; Work; Writing; cancer cell; career; career development; cell type; chemotherapy; deprivation; experimental study; extracellular; improved; improved outcome; in vivo; metabolic abnormality assessment; metabolomics; mouse model; novel; novel strategies; novel therapeutics; oxidation; programs; research and development; response; skills; tumor; tumor metabolism; tumor progression; wound healing

PROJECT SUMMARY/ABSTRACT The ability of fibroblasts to synthesize extracellular matrix (ECM) proteins is critical for wound healing; however, this program is coopted by cancer cells in multiple solid tumors, resulting in the formation of cancer-associated fibroblasts (CAFs) that drive a desmoplastic response which contributes to cancer progression and promotes therapy resistance. Collagen is the most abundant protein in the ECM and has a unique amino acid composition such that up to 25% of its sequence is represented by proline. Proline is a limiting metabolite for collagen synthesis in CAFs, and CAFs promote proline biosynthesis by increasing mitochondrial glutaminolysis and directing the resulting glutamate into the proline biosynthetic pathway instead of its utilization as an anaplerotic substrate for the TCA cycle. However, the mechanism directing the differential utilization of glutamine for proline or the TCA cycle is not understood. Besides, glutamine is depleted in many solid tumors such as pancreatic ductal adenocarcinoma (PDAC), but paradoxically, collagen is highly abundant in PDAC. The objective of the present proposal is to gain a better understanding of the unique metabolic requirements for collagen production in CAFs and thereby identify novel targets to reduce tumor desmoplasia. The proposed studies are aimed at determining how CAFs redirect glutamine into proline biosynthesis (Aim 1) and identifying the adaptive mechanisms by which CAFs sustain collagen production when extracellular glutamine is limited (Aim 2). Finally, I will investigate whether targeting these adaptive mechanisms is a strategy to reduce desmoplasia in PDAC without affecting matrix production in healthy tissues (Aim 3). The scientific knowledge gained from these studies as well as my research training plan will help me to develop a unique research program and facilitate transition into to independence, with the long-term goal to study the mechanistic basis of tumor-stroma crosstalk and to apply this knowledge to develop therapeutic strategies that can improve outcomes of cancer patients. In addition to my research objectives, I have outlined a detailed career development plan that will help me obtain important skills for leading an independent research laboratory, including teaching and mentoring skills, scientific communications, grant writing and laboratory management. I will work towards my goals under the mentorship of Dr. Craig Thompson, a leader in cancer metabolism with a stellar track record of trainees that went on to faculty positions. In addition, I have assembled an Advisory Committee that will collaborate and meet with me regularly to help me perform the proposed experiments and develop into an independent researcher. This team includes Dr. Justin Cross with expertise in metabolomics, Dr. Scott Lowe with expertise in mouse models of cancer, Dr. Joshua Rabinowitz with expertise in studying metabolic flux in vivo, and Dr. Gina Sizemore with expertise in studying tumor-stroma interactions. My research and career development plan, together with my mentor, advisors and the exceptional academic environment at Memorial Sloan Kettering Cancer Center will provide a solid ground on which I can build a career as an independent investigator in cancer metabolism.

项目概要/摘要 成纤维细胞合成细胞外基质（ECM）蛋白的能力对于伤口愈合至关重要；然而， 该程序被多个实体瘤中的癌细胞吸收，导致形成癌症相关的 成纤维细胞 (CAF) 驱动促纤维增生反应，促进癌症进展并促进 治疗抵抗。胶原蛋白是 ECM 中最丰富的蛋白质，具有独特的氨基酸组成 使得其序列的高达 25% 由脯氨酸代表。脯氨酸是胶原蛋白的限制代谢物 CAF 中的合成，CAF 通过增加线粒体谷氨酰胺分解和促进脯氨酸生物合成 将所得谷氨酸引导至脯氨酸生物合成途径，而不是用作回补剂 TCA循环的底物。然而，指导谷氨酰胺对脯氨酸的差异利用的机制 或者TCA循环不被理解。此外，谷氨酰胺在许多实体瘤（例如胰腺癌）中被耗尽。 导管腺癌（PDAC），但矛盾的是，PDAC 中胶原蛋白含量很高。该计划的目标 目前的建议是为了更好地了解胶原蛋白生成的独特代谢要求 从而确定减少肿瘤结缔组织形成的新靶点。拟议的研究旨在 确定 CAF 如何将谷氨酰胺重定向为脯氨酸生物合成（目标 1）并确定适应性 当细胞外谷氨酰胺有限时，CAF 维持胶原蛋白生成的机制（目标 2）。最后， 我将研究针对这些适应性机制是否是减少 PDAC 结缔组织增生的策略 而不影响健康组织中的基质生成（目标 3）。从这些研究中获得的科学知识 我的研究培训计划将帮助我制定独特的研究计划并促进过渡 独立，长期目标是研究肿瘤间质串扰的机制基础并 应用这些知识来制定可以改善癌症患者预后的治疗策略。此外 为了我的研究目标，我制定了详细的职业发展计划，该计划将帮助我获得重要的 领导独立研究实验室的技能，包括教学和指导技能、科学技能 沟通、资助写作和实验室管理。我会在导师的指导下朝着我的目标努力 克雷格·汤普森 (Craig Thompson) 博士是癌症代谢领域的领导者，在受训者中拥有出色的记录 教师职位。此外，我还组建了一个咨询委员会，该委员会将与我合作并会面 定期帮助我执行建议的实验并发展成为一名独立研究员。这支球队 其中包括具有代谢组学专业知识的 Justin Cross 博士、具有小鼠模型专业知识的 Scott Lowe 博士 Joshua Rabinowitz 博士在研究体内代谢通量方面拥有丰富的专业知识，Gina Sizemore 博士则在癌症领域拥有丰富的研究经验 研究肿瘤-基质相互作用的专业知识。我的研究和职业发展计划，以及我的 纪念斯隆凯特琳癌症中心的导师、顾问和卓越的学术环境将 为我作为癌症代谢领域的独立研究者奠定了坚实的基础。