Propionate metabolism and cancer

丙酸代谢与癌症

基本信息

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
项目类别：
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

项目摘要

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（最多 30 行）绝大多数癌症死亡是由于转移造成的。肿瘤学中一个未满足的主要需求是如何预测。为了满足这一需求，我们必须加深对如何预防转移的理解。肿瘤细胞获得转移能力是一种正常的生理现象。伤口愈合和发育过程中，极化上皮细胞经历生化、代谢、和表观遗传变化并转化为间充质表型，其特征是增强的迁移和癌症利用这种重编程来获得转移能力。细胞经历 EMT 对于揭示癌症如何发生转移至关重要。但最近的工作重点关注引发 EMT 和转移的基因突变或基因表达变化。表明代谢物等非遗传因素可以促进癌症进展，这表明尚未探索深入了解 EMT 并捕捉必要的连续变化。为了使癌症发生转移，我们多次进行蛋白质组学、代谢组学和转录组学我们的多方面方法揭示了丙酸的丰富新见解。事实上，EMT 期间代谢失调，我们观察到丙酰辅酶 A 和甲基丙二酸增加。酸（MMA），丙酸代谢的二羧酸副产物，在早期 EMT 过程中测试功能。升高的 MMA 的影响，我们用 MMA 治疗肺癌和乳腺癌细胞，令人惊讶的是，我们发现 MMA。在我们发现之前，人们对此知之甚少。丙酸代谢和丙酸代谢以外的MMA在罕见的先天性缺陷中失调代谢统称为“甲基丙二酸血症”。最近的一些研究还表明，据我们所知，我们的研究结果表明，血清中的 MMA 会随着年龄的增长而增加，并且与年龄相关的全因死亡率有关。第一个证明丙酸代谢在 EMT 和癌细胞进展中发挥作用。引导我们研究丙酸代谢在 EMT 期间如何改变。我们的长期目标是确定这种改变。途径受到多种转移诱导剂和途径中多个点的调节，并定义如何癌细胞产生的 MMA 也会影响肿瘤微环境。满足更好地了解转移的分子基础的迫切需要。我们的期望是。成功完成拟议的工作将通过改变范式和影响癌症生物学我们的工作将重点关注驱动癌症进展的关键非遗传因素，并找出新的因素。可用于预防和抑制转移的生物标志物和治疗靶点。