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

项目摘要/摘要 肿瘤和间质细胞之间的代谢相互作用和共同进化是一个未被探索的话题。 它结合了癌症新陈代谢和肿瘤微环境。拟议的项目将对此进行调查 从细胞外miRNAs的新视角看癌症-宿主串扰的独特方面，其在 将癌症信号传递给各种类型的利基细胞以促进肿瘤的生长和转移 最近得到了认可。MiRNA通过诱导mRNA负向调节基因表达 降级和/或翻译封锁。这项研究的目标是确定通过什么机制 癌细胞分泌的miRNAs指导间质成纤维细胞的代谢可塑性，以参与不同的 不同代谢条件下肿瘤-间质相互作用的模式，并检测潜力 针对这一过程的治疗干预。在目标1中，我们将确定其作用机制 特定乳腺癌(BC)分泌的miRNAs在癌症相关代谢重编程中的作用 成纤维细胞(CAF)，包括一种通过激活MYC指导的代谢程序的机制。在目标2中，我们 将表征BC细胞和重新编程的CAF在不同代谢情况下的代谢相互作用 使用稳定同位素示踪和细胞共培养的条件。选定miRNAs的具体作用以及 他们的目标基因将通过遗传修饰和药物抑制来确定。在《目标3》中，我们将 评价已确定的miRNA调节通路的体内效应及其药理作用 联合移植BC和CAF细胞对肿瘤生长和进展的抑制作用 病人。我们还将研究选定的miRNAs和代谢基因/调节因子之间的关联 以及相应血清样本中这些miRNAs的循环水平。这个 所提出的研究将为我们理解动态交流提供一个新的视角 癌症与宿主以及癌症对代谢疗法的反应，并将为新的 减缓或阻止BC进展的治疗策略，这是我们的长期目标。临床期抑制药 将检查它们阻止癌症-间质代谢相互作用和抑制肿瘤的效果 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.