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: 10375560
• 负责人: Simon Schwörer
• 金额: $ 10.91万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375560
• 关键词: Advisory Committees; Affect; Amino Acids; Anabolism; Award; Bioenergetics; Biology; Cancer Model; Cancer Patient; Carbon; Citric Acid Cycle; 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; Oxides; 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; Vascular blood supply; Vertebral column; Work; Writing; base; 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.

项目总结/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， 该程序被多种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）驱动促结缔组织增生反应，导致癌症进展并促进 治疗抵抗胶原蛋白是ECM中含量最丰富的蛋白质，具有独特的氨基酸组成 使得高达25%的序列由脯氨酸代表。脯氨酸是胶原蛋白的限制代谢物 CAFs中的脯氨酸合成，CAFs通过增加线粒体的脯氨酸分解促进脯氨酸的生物合成， 将所得的谷氨酸导入脯氨酸生物合成途径，而不是将其用作回补剂。 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如胰腺癌中被耗尽。 导管腺癌（PDAC），但矛盾的是，胶原蛋白是高度丰富的PDAC。的目的 目前的建议是更好地了解胶原蛋白生产的独特代谢要求 在CAF中，从而鉴定减少肿瘤结缔组织增生的新靶点。拟议的研究旨在 确定CAFs如何将谷氨酰胺重定向到脯氨酸生物合成（Aim 1），并确定适应性的 当细胞外谷氨酰胺受到限制时，CAF维持胶原蛋白产生的机制（目的2）。最后， 我将研究是否针对这些适应性机制是一种策略，以减少结缔组织增生的PDAC 而不影响健康组织中的基质产生（目标3）。从这些研究中获得的科学知识 以及我的研究培训计划将帮助我制定一个独特的研究计划，并促进过渡 长期目标是研究肿瘤-间质串扰的机制基础， 将这些知识应用于开发可以改善癌症患者结果的治疗策略。此外 根据我的研究目标，我已经制定了一个详细的职业发展计划，这将有助于我获得重要的 领导独立研究实验室的技能，包括教学和指导技能，科学 通信、赠款撰写和实验室管理。我将在导师的指导下朝着我的目标努力 克雷格汤普森博士，癌症代谢的领导者，有着出色的受训记录， 教师职位。此外，我还组建了一个咨询委员会， 定期帮助我进行拟议的实验，并发展成为一个独立的研究人员。这支球队 包括Justin Cross博士在代谢组学方面的专业知识，Scott Lowe博士在小鼠模型方面的专业知识， 癌症，约书亚Rabinowitz博士在研究体内代谢通量的专业知识，和吉娜Sizemore博士与 研究肿瘤间质相互作用的专业知识。我的研究和职业发展计划，连同我的 导师，顾问和特殊的学术环境在纪念斯隆凯特琳癌症中心将 这为我作为一名独立的癌症代谢研究者奠定了坚实的基础。