Propionate metabolism as an essential metabolic adaptation for tumor progression

丙酸代谢作为肿瘤进展的重要代谢适应

• 批准号: 10457486
• 负责人: Ana da silva Gomes
• 金额: $ 24.9万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457486
• 关键词: Acids; Adjuvant Therapy; Affect; Amino Acids; Award; Breast Cancer Cell; Breast Epithelial Cells; Cancer Biology; Cancer Etiology; Carcinoma; Catabolism; Cell Survival; Cells; Citric Acid Cycle; Complex; Data; Dependence; Development; Dicarboxylic Acids; Disease; Distant; Elderly; Enzymes; Fatty Acids; Genetic; Goals; Grant; Growth; Immune system; Immunology; Immunosuppressive Agents; Invaded; Isogenic transplantation; Isotopes; Laboratories; Lead; Learning; Malignant Epithelial Cell; Malignant Neoplasms; Mentors; Metabolic; Metabolic Pathway; Metabolism; Metastatic breast cancer; Metastatic to; Methylmalonic Acid; Molecular; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Paper; Pathology; Pathway interactions; Peer Review; Phase; Physiological; Plasma; Play; Primary Neoplasm; Process; Production; Property; Propionates; Publishing; Reaction; Regulation; Research; Role; Series; Serum; Signal Pathway; Signal Transduction; Site; Stimulus; Technology; Testing; Training; Work; Writing; Xenograft procedure; addiction; cancer cell; cancer type; epithelial to mesenchymal transition; in vivo; methylmalonyl-CoA decarboxylase; mortality; mouse model; neoplastic cell; programs; propionyl-coenzyme A; skills; succinyl-coenzyme A; therapeutic target; therapy resistant; tumor; tumor immunology; tumor metabolism; tumor microenvironment; tumor progression; tumorigenesis

PROJECT SUMMARY/ ABSTRACT The current understanding of how primary tumor cells acquire the capacity to metastasize is still very limited. This becomes a major problem to find effective cures for all types of cancer, as metastatic disease accounts for the majority of cancer-related mortality. Therefore, a deep understanding of the changes that occur in primary tumor cells that lead them to acquire the ability to escape the immune system, migrate, invade, colonize and survive at distant niches is necessary. Metabolic reprogramming is at the intersection of signaling pathways and their ability to elicit cellular changes to promote increased cell survival, growth and proliferation. However, which metabolic adaptations are necessary to enable cancer cells to create a permissive microenvironment and survive the arduous process that leads to metastases remains poorly understood. Here, I propose that increased propionate metabolism is an essential metabolic adaptation that drives tumor progression and ultimately leads to metastasis. My preliminary data show that not only is increased propionate metabolism crucial for the acquisition of metastatic properties, but also that metastatic breast cancer cells are “addicted” to this pathway. Therefore, my goal is to understand how pathways that drive metastasis regulate propionate metabolism and what functions increased propionate metabolism has during tumor progression. During the K99 phase of this award, I will determine the molecular mechanisms that regulate propionate metabolism and will evaluate if propionate metabolism affects metastasis formation in vivo. During the R00 phase of this award, I will focus on understanding what key functional roles propionate metabolism serves to support tumor progression and the development of metastases. This work will establish a new branch of metabolic signaling and expand our understanding of metabolic dependencies and their role during tumor progression. In addition to the scientific goals of this proposal, I have also proposed a comprehensive training plan during the K99 phase of the award that will prepare me for the transition to independence. This includes guidance from three renowned mentors, Drs. John Blenis, Lewis Cantley and Douglas Fearon, acquisition of new skills in immunology and the study of tumor microenvironment, training on state-of-the-art technology for isotope tracing, and development of professional skills to guide my transition to independence.

项目摘要/摘要 目前对原代肿瘤细胞如何获得转移能力的了解仍然非常有限。 这成为为所有类型的癌症找到有效的治疗方法的主要问题，因为转移性疾病 与癌症相关的大部分死亡人数。因此，对发生在 导致它们获得逃避免疫系统、迁移、侵袭、 在遥远的小生境中殖民和生存是必要的。新陈代谢重新编程处于信号的交叉点 途径及其引发细胞变化的能力，以促进细胞的存活、生长和增殖。 然而，哪些代谢适应是必要的，使癌细胞能够产生允许的 在导致转移的艰难过程中存活下来的微环境仍然知之甚少。 在这里，我认为丙酸代谢增强是推动肿瘤发生的一种重要的代谢适应。 进展并最终导致转移。我的初步数据显示，不仅丙酸含量增加 新陈代谢对于获得转移特性至关重要，但也说明转移的乳腺癌细胞 对这条路“上瘾”。因此，我的目标是了解驱动转移的通路是如何调控的 丙酸代谢以及在肿瘤进展过程中增加丙酸代谢的功能。 在这个奖项的K99阶段，我将确定调节丙酸的分子机制 并将评估丙酸代谢是否会影响体内转移的形成。在R00期间 在这个奖项的阶段，我将重点了解丙酸代谢在哪些方面起关键作用 支持肿瘤的进展和转移的发展。这项工作将建立一个新的分支机构 代谢信号和扩大我们对代谢依赖性及其在肿瘤中的作用的理解 进步。除了这项建议的科学目标外，我还提出了一项全面的培训 在K99奖项阶段的计划，将使我为向独立过渡做好准备。这包括 在三位著名导师John Blenis、Lewis坎特利和Douglas Fearon博士的指导下，收购了 免疫学和肿瘤微环境研究的新技能，最先进技术的培训 同位素追踪，以及专业技能的发展，引导我向独立过渡。