Role of breast cancer-secreted miRNA in directing a stromal metabolic plasticity

项目概要/摘要 发生在肿瘤和基质细胞之间的代谢相互作用和共同进化是一个尚未探索的课题 结合了癌症代谢和肿瘤微环境。拟议项目将对此进行调查 从细胞外miRNAs的新角度来看，癌症-宿主串扰的独特方面，其在 将癌症衍生的信号转移到各种类型的小生境细胞以促进癌症生长和转移 最近得到了承认。miRNA通过诱导mRNA负调控基因表达 降解和/或翻译封锁。本研究的目的是确定 癌细胞分泌的miRNA指导基质成纤维细胞的代谢可塑性， 不同代谢条件下的癌症-间质相互作用模式，并检查潜在的 针对这一过程的治疗干预。在目标1中，我们将确定 选择乳腺癌（BC）分泌的miRNA在癌症相关的代谢重编程中的作用 成纤维细胞（CAF），包括通过激活MYC指导的代谢程序的机制。在目标2中， 将表征不同代谢下BC细胞和重编程CAF之间的代谢相互作用 使用稳定同位素示踪和细胞共培养的条件。选择的miRNAs的特定作用以及 它们的靶基因将通过遗传修饰和药理学抑制来确定。在目标3中，我们 评价本文鉴定的miRNA调节途径的体内作用，以及它们的药理学作用。 抑制，对肿瘤生长和进展的影响，使用来自 患者我们还将研究选定的miRNAs和代谢基因/调节因子之间的关联， 人BC，以及这些miRNA在相应血清样品中的循环水平。的 提出的研究将提供一个新的视角，我们之间的动态通信的理解 癌症和宿主以及癌症对代谢疗法的反应，并将建立新的理论基础。 治疗策略，以减缓或停止BC进展，这是我们的长期目标。临床阶段抑制剂 将检查它们阻断癌症-间质代谢相互作用和抑制肿瘤的作用 进展，这允许快速转化为未来的临床试验。

PROJECT SUMMARY/ABSTRACT The metabolic interactions and coevolution that occur between cancer and stromal cells is an unexplored topic that combines cancer metabolism and tumor microenvironment. The proposed project will investigate this unique aspect of cancer–host crosstalk from the novel perspective of extracellular miRNAs, whose function in transferring cancer-derived signals to various types of niche cells to facilitate cancer growth and metastasis has been recently recognized. MiRNA negatively regulates gene expression through inducing mRNA degradation and/or translation blockade. The goals of this study are to identify the mechanisms by which cancer cell-secreted miRNAs direct a metabolic plasticity in stromal fibroblasts to engage different modes of cancer–stroma interactions under different metabolic conditions, and to examine potential therapeutic interventions targeting this process. In Aim 1, we will determine the acting mechanisms of selected breast cancer (BC)-secreted miRNAs in the metabolic reprogramming of cancer-associated fibroblasts (CAFs), including a mechanism through activation of MYC-directed metabolic program. In Aim 2, we will characterize the metabolic interplays between BC cells and reprogrammed CAFs under different metabolic conditions using stable isotope tracing and cell co-cultures. The specific role of selected miRNAs as well as their target genes will be determined by genetic modifications and pharmacological inhibition. In Aim 3, we will evaluate the in vivo effects of the herein identified miRNA-regulated pathways, as well as their pharmacological inhibition, on tumor growth and progression using models of co-transplanted BC and CAF cells derived from patients. We will also examine the associations among selected miRNAs and metabolic genes/regulators in human BCs, as well as the circulating levels of these miRNAs in the corresponding serum samples. The proposed studies will provide a novel perspective to our understanding of the dynamic communication between cancer and host as well as cancer's response to metabolic therapies, and will establish rationales for novel therapeutic strategies to slow or stop BC progression, which is our long-term objective. Clinical-stage inhibitors will be examined for their effects to block cancer–stroma metabolic interactions and suppress tumor progression, which allows rapid translation into future clinical trials.