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 当前对原发性肿瘤细胞如何获得转移能力的理解仍然非常有限。 这成为为所有类型癌症找到有效治疗方法的主要问题，因为转移性疾病的记录 对于大多数与癌症相关的死亡率。因此，对发生的变化有深刻的理解 导致他们获得免疫系统，迁移，入侵的能力的原发性肿瘤细胞， 有必要在遥远的壁nir中殖民并生存。代谢重编程是在信号传导的交汇处 途径及其引起细胞变化以促进细胞存活，生长和增殖的能力。 但是，对于使癌细胞创建允许的，需要哪种代谢适应 微环境和在导致转移的振奋过程中幸存下来仍然很少了解。 在这里，我建议增加丙酸代谢是驱动肿瘤的必不可少的代谢适应 进展并最终导致转移。我的初步数据表明，不仅是丙酸 代谢对于获取转移性特性至关重要，但也认为转移性乳腺癌细胞是 这条路“上瘾”。因此，我的目标是了解驱动转移的途径如何调节 丙酸代谢以及在肿瘤进展过程中丙酸代谢增加的功能增加。 在此奖项的K99阶段，我将确定调节丙酸的分子机制 代谢并将评估丙酸代谢是否影响体内转移形成。在R00期间 该奖项的阶段，我将专注于理解丙酸代谢的主要功能角色 支持肿瘤进展和转移的发展。这项工作将建立一个新的分支 代谢信号传导并扩展我们对代谢依赖性及其在肿瘤中的作用的理解 进展。除了该提案的科学目标外，我还提出了全面的培训 在奖励的K99阶段计划，这将使我为过渡到独立做准备。这包括 来自三位著名导师的指导，博士。约翰·布莱尼斯（John Blenis），刘易斯·坎特利（Lewis Cantley）和道格拉斯·弗罗斯（Douglas Fearon），收购 免疫学和肿瘤微环境研究的新技能，有关最先进技术的培训 同位素追踪以及发展专业技能以指导我过渡到独立性。