Propionate metabolism and cancer

概要（最多30行） 绝大多数癌症死亡是由于转移。肿瘤学的一个主要未满足的需求是如何预测 并防止转移性进展。为了满足这一需求，我们必须进一步了解如何 肿瘤细胞获得转移能力。上皮细胞向间质细胞转化（EMT）是一种正常的生理过程， 伤口愈合和发展的过程，极化的上皮细胞通过该过程经历生物化学，代谢， 和表观遗传变化并转化为间充质表型，其特征在于增强的迁移和 入侵能力。癌症利用这种重编程来获得转移能力。了解肿瘤 细胞经历EMT对于揭示癌症如何转移至关重要。从历史上看， 主要集中在引发EMT和转移的基因突变或基因表达变化。但最近的研究表明， 表明非遗传因素，如代谢物，可以促进癌症进展，这表明未探索 癌症生物学领域。为了更深入地了解EMT并捕获必要的顺序更改， 对于癌症的转移，我们在多个时间点进行了蛋白质组学、代谢组学和转录组学研究， 点作为细胞进行EMT。我们的多方面方法揭示了丰富的新见解。我们发现丙酸盐 EMT期间代谢失调。事实上，我们观察到丙酰辅酶A和甲基丙二酸 酸（MMA），丙酸代谢的二羧酸副产物，在早期EMT。测试功能 由于MMA升高的影响，我们用MMA处理肺癌和乳腺癌细胞。令人惊讶的是，我们发现MMA 引发了EMT并增强了迁移和入侵能力。在我们发现之前， 丙酸代谢和MMA以外的丙酸代谢失调的罕见先天性缺陷， 代谢统称为“甲基丙二酸酯”。最近的一些研究也表明， MMA随着年龄的增长而增加，并与年龄相关的全因死亡率有关。据我们所知，我们的发现 首次证明丙酸代谢在EMT和癌细胞进展中起作用。这 引导我们研究丙酸代谢在EMT期间是如何改变的。我们的长期目标是确定 该通路受多种转移诱导物的调节，并在通路的多个点进行调节， 癌细胞产生的MMA也可以影响肿瘤微环境。我们建议的研究将 解决了更好地理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来影响癌症生物学， 突出了推动癌症进展的关键非遗传因素。因此，我们的工作将确定新的 生物标志物和治疗靶点，可用于预防和抑制转移。

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.