Propionate metabolism and cancer

丙酸代谢与癌症

• 批准号: 10660197
• 负责人: JOHN BLENIS
• 金额: $ 63.44万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-25 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660197
• 关键词: Address; Age; Area; Automobile Driving; Biochemical; Biological Markers; Biological Process; Biology; Branched-Chain Amino Acids; Breast Cancer Cell; Cancer Biology; Cause of Death; Cells; Cessation of life; Chemoresistance; Communication; Coupled; DNA Sequence Alteration; Data; Development; Dicarboxylic Acids; Disease; Disseminated Malignant Neoplasm; Drug Targeting; Drug resistance; Elderly; Enzymes; Epigenetic Process; Epithelial Cells; Expression Profiling; Fatty Acids; Fibroblasts; Gene Expression; Genetic; Genetic Transcription; Goals; Hereditary Disease; Hypoxia; In Vitro; Inborn Errors of Metabolism; Knowledge; Link; MAPK1 gene; Malignant Neoplasms; Mesenchymal; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Molecular; Neoplasm Metastasis; Oncology; Pathway interactions; Patients; Persons; Phenotype; Physiological Processes; Primary Neoplasm; Process; Production; Property; Propionates; Proteomics; Publishing; Regulator Genes; Serum; Signal Transduction; Solid Neoplasm; Testing; Therapeutic Intervention; Time; Tumor Promotion; Work; age related; autocrine; cancer cell; cancer therapy; drug discovery; epimerase; epithelial to mesenchymal transition; expectation; extracellular; improved; in vivo; in vivo Model; insight; lung cancer cell; metabolome; metabolomics; methylmalonic aciduria; methylmalonyl-CoA decarboxylase; methylmalonyl-coenzyme A; mortality; neoplastic cell; non-genetic; novel; nutrient deprivation; paracrine; personalized therapeutic; prevent; programs; propionyl-coenzyme A; targeted treatment; therapeutic target; transcriptomics; tumor; tumor growth; tumor microenvironment; tumor progression; wound healing

SUMMARY (30 lines max) The vast majority of cancer mortality is due to metastases. A major unmet need in oncology is how to predict and prevent metastatic progression. To address this need, it is imperative we advance our understanding of how tumor cells acquire metastatic capability. Epithelial-to-mesenchymal transition (EMT) is a normal physiologic process in wound healing and development by which polarized epithelial cells undergo biochemical, metabolic, and epigenetic changes and convert to a mesenchymal phenotype, characterized by enhanced migratory and invasive capacity. Cancers co-opt this reprogramming to acquire metastatic ability. Understanding how tumor cells undergo EMT is critical to unraveling how cancer becomes metastatic. Historically, studies have primarily focused on genetic mutations or gene expression changes that trigger EMT and metastasis. But recent work has suggested that non-genetic factors such as metabolites can promote cancer progression, suggesting unexplored areas of cancer biology. To gain a deeper understanding of EMT and capture the sequential changes necessary for cancer to become metastatic, we performed proteomics, metabolomics and transcriptomics at multiple time points as cells underwent EMT. Our multifaceted approach revealed rich new insights. We found that propionate metabolism was dysregulated during EMT. Indeed, we observed increased propionyl-CoA and methylmalonic acid (MMA), a dicarboxylic acid by-product of propionate metabolism, during early EMT. To test the functional effect of elevated MMA, we treated lung and breast cancer cells with MMA. Strikingly, we found that MMA triggered EMT and enhanced migratory and invasive capacity. Prior to our discovery, little was known about propionate metabolism and MMA other than propionate metabolism is dysregulated in rare inborn errors of metabolism collectively referred to as “methylmalonic acidemias.” Some recent studies have also shown that MMA increases in serum with age and is linked to age-related, all-cause mortality. To our knowledge, our findings are the first to demonstrate that propionate metabolism plays a role in EMT and cancer cell progression. This led us to study how propionate metabolism is altered during EMT. Our long-term goals are to define how this pathway is regulated by multiple inducers of metastasis and at multiple points in the pathway, and to define how MMA produced by cancer cells can also influence the tumor microenvironment. Our proposed studies will address a critical need for a greater understanding of the molecular basis of metastasis. Our expectations are that successful completion of the proposed work will impact cancer biology by shifting the paradigm and highlighting critical non-genetic factors that drive cancer progression. Consequently, our work will identify new biomarkers and therapeutic targets that can be exploited to prevent and inhibit metastases.

摘要（最大30行） 绝大多数癌症死亡率是由于转移造成的。肿瘤学的主要未满足需求是如何预测 并防止转移进展。为了满足这一需求，我们必须提高我们对如何的理解 肿瘤细胞具有转移性能力。上皮到间质转变（EMT）是一种正常的生理 伤口愈合和发育的过程，两极分化的上皮细胞经历生化，代谢， 和表观遗传变化并转化为间充质表型，其特征是迁徙和 入侵能力。癌症选择此重编程以获得转移能力。了解肿瘤如何 细胞进行EMT对于揭示癌症如何转移性至关重要。从历史上看，研究主要 专注于遗传突变或基因表达变化，触发EMT和转移。但是最近的工作有 建议非代谢产物等非遗传因素可以促进癌症的进展，表明意外 癌症生物学领域。要深入了解EMT并捕获必要的顺序变化 为了使癌症成为转移性，我们多次进行了蛋白质组学，代谢组学和转录组学 点为细胞接受EMT。我们的多方面方法揭示了丰富的新见解。我们发现丙酸 在EMT期间，代谢失调。实际上，我们观察到丙酰辅酶A和甲基丙二酰丙二烷增加 酸（MMA），丙酸二羧酸的丙酸代谢副产品，在EMT早期。测试功能 MMA升高的影响，我们用MMA治疗了肺和乳腺癌细胞。令人惊讶的是，我们发现MMA 触发EMT并增强了迁徙和侵入性能力。在我们发现之前，对 除丙酸新陈代谢以外的丙酸代谢和MMA中，在罕见的先天错误中失调 代谢统称为“甲基丙二烷酸血压”。最近的一些研究还表明 MMA随着年龄的增长而增加血清，并与年龄相关的全因死亡率有关。据我们所知，我们的发现 是第一个证明丙酸代谢在EMT和癌细胞进展中起作用的人。这 导致我们研究了EMT期间如何改变丙酸代谢。我们的长期目标是定义如何 途径由多个转移的影响者和途径的多个点调节，并定义如何定义 癌细胞产生的MMA也会影响肿瘤微环境。我们提出的研究将 解决了对转移分子基础的更多了解的关键需求。我们的期望是 成功完成拟议的工作将通过移动范式和 强调促进癌症进展的关键非遗传因素。因此，我们的工作将确定新的 可以探索以预防和抑制转移的生物标志物和治疗靶标。