Propionate metabolism as an essential metabolic adaptation for tumor progression

项目总结/摘要 目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。 这成为一个主要问题，以找到有效的治疗所有类型的癌症，作为转移性疾病帐户 导致了大多数癌症相关死亡。因此，深入了解发生的变化 原发性肿瘤细胞，使它们获得逃避免疫系统，迁移，入侵， 在遥远的小生境中殖民和生存是必要的。代谢重编程是在信号的交叉点 它们可以通过调节细胞内信号通路和它们引发细胞变化以促进增加的细胞存活、生长和增殖的能力来调节。 然而，哪些代谢适应是必要的，使癌细胞能够创造一个允许的 微环境和生存的艰苦过程，导致转移仍然知之甚少。 在这里，我认为丙酸代谢的增加是一种重要的代谢适应， 进展并最终导致转移。我的初步数据显示丙酸盐的增加 代谢对于获得转移性特性至关重要，而且转移性乳腺癌细胞 对这条路“上瘾”。因此，我的目标是了解驱动转移的途径如何调节 丙酸代谢以及丙酸代谢增加在肿瘤进展过程中的作用。 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影响体内转移形成。在R 00期间 在这个奖项的第一阶段，我将专注于了解丙酸代谢的关键功能作用， 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，扩大我们对代谢依赖性及其在肿瘤发生中的作用的理解。 进展除了这个科学的目标建议之外，我还提出了一个全面的训练 在K99阶段的奖励计划，将准备我过渡到独立。这包括 在三位著名导师John Blenis、刘易斯坎特利和道格拉斯费伦博士的指导下， 免疫学和肿瘤微环境研究的新技能，最先进技术的培训， 同位素追踪和专业技能的发展，以指导我过渡到独立。

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.