Roles of mRNA Transfer in Cancer Cell-Platelet Communication

mRNA 转移在癌细胞-血小板通讯中的作用

• 批准号: 10748535
• 负责人: Ren Xu
• 金额: $ 40.19万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748535
• 关键词: Affinity Chromatography; Binding Proteins; Biological Assay; Biology; Blood Platelets; Breast Cancer Cell; CXC Chemokines; CXCR4 Receptors; CXCR4 gene; Cancer Patient; Cell Communication; Cell fusion; Cell physiology; Cells; Co-Immunoprecipitations; Communication; Complex; Cytokine Activation; Data; Distant; Family; Galectin 3; Genes; Genetic Engineering; Hematogenous; Incidence; Knockout Mice; Knowledge; Malignant Neoplasms; Mediating; Membrane Fusion; Membrane Proteins; Messenger RNA; MicroRNAs; Microfluidic Microchips; Molecular; Neoplasm Circulating Cells; Neoplasm Metastasis; Organ; PF4 Gene; Pathway Analysis; Pathway interactions; Play; Population; Positioning Attribute; Primary Neoplasm; Proteins; Recurrence; Regulation; Research; Ribosomes; Role; Signal Transduction; Small RNA; Stromal Cell-Derived Factor 1; Testing; Tissues; Translating; Translations; breast cancer progression; cancer cell; cancer genetics; carcinogenesis; chemokine; confocal imaging; cytokine; extracellular vesicles; gain of function; genetic signature; human data; in vivo; inhibitor; insight; intercellular communication; loss of function; mRNA delivery; malignant breast neoplasm; mouse model; multidisciplinary; neoplastic cell; novel; novel strategies; protein complex; recruit; screening; small molecule; stemness; therapeutic target; tissue culture; transcriptome sequencing; tumor progression

The interaction between cancer cells and platelets plays important roles in regulating cancer cell function. Understanding how platelets communicate with cancer cells to modulate cancer cell colonization at distant organs may identify novel strategies to halt cancer spreading. We recently showed that recruitment of platelet to cancer cells is essential for the colonization of circulating tumor cells (CTCs) at the secondary organs. However, the molecular mechanism by which platelets modulate cancer cell function to promote cancer cell colonization remains to be determined. By analyzing RNA-seq data from CTCs and primary tumors, we found that platelet- specific mRNA was significantly enriched in CTCs. RNAscope and Translating Ribosome Affinity Purification (TRAP) analyses showed the delivery of platelet mRNA and translation of platelet-derived mRNA in cancer cells. In vivo functional screening identified multiple platelet-derived mRNAs contribute to colonization of breast cancer cell at distant organs. These results reveal the new role of platelet mRNA in mediating intercellular communication and in promoting cancer cell spreading. The overall objective of this proposal is to define the molecular mechanism by which platelet mRNA is delivered into breast cancer cells and determine roles of platelet mRNA as the signaling molecular in promoting cancer cell colonization at distant organs. We showed that CD9 expression in CTCs correlated with the accumulation of platelet-specific mRNA. Silencing CD9 in breast cancer cells significantly reduced platelet mRNA transferring and colonization of cancer cells. Platelet factor 4 (PF4) is a small cytokine belonging to the CXC chemokine family that is highly expressed in platelets. We showed that the transfer of PF4 mRNA from platelets to breast cancer cells enhanced stemness and colonization of cancer cells. Based on these results, the central hypothesis of this proposal is that the CD9-dependent mRNA transfer mediates the platelet-cancer cell communication and promotes cancer cell stemness. We propose the following two aims to test this hypothesis and achieve our objective. Aim 1. Elucidate the mechanism by which platelet mRNA is transferred into cancer cells. Aim 2. Determine how the transfer of platelet PF4 mRNA in cancer cells promotes cancer metastasis.

癌细胞和血小板之间的相互作用在调节癌细胞功能方面起着重要作用。 了解血小板与癌细胞如何在远处调节癌细胞定植 器官可以确定制止癌症扩散的新型策略。我们最近表明，血小板招募到 癌细胞对于继发器官循环肿瘤细胞（CTC）的定殖至关重要。然而， 血小板调节癌细胞功能以促进癌细胞定植的分子机制 仍有待确定。通过分析来自CTC和原发性肿瘤的RNA-seq数据，我们发现血小板 特异性mRNA在CTC中显着富集。 rnascope和翻译核糖体亲和力净化 （陷阱）分析显示血小板mRNA的递送和癌细胞中血小板衍生的mRNA的翻译。 体内功能筛查确定了多个血小板衍生的mRNA，有助于乳腺癌定殖 远处器官的细胞。这些结果揭示了血小板mRNA在介导细胞间中的新作用 交流和促进癌细胞扩散。该提议的总体目的是定义 将血小板mRNA传递到乳腺癌细胞中并确定血小板的作用的分子机制 mRNA作为促进远处器官癌细胞定植的信号传导分子。我们证明了CD9 CTC中的表达与血小板特异性mRNA的积累相关。沉默乳腺癌的CD9 细胞显着降低了癌细胞的血小板mRNA转移和定植。血小板因子4（PF4）为 属于CXC趋化因子家族的小细胞因子，在血小板中高度表达。我们表明了这一点 PF4 mRNA从血小板转移到乳腺癌细胞，增强了癌症的干性和定殖 细胞。基于这些结果，该提议的中心假设是CD9依赖性mRNA转移 介导血小板癌细胞的通信并促进癌细胞干。我们提出以下内容 两个目的是检验这一假设并实现我们的目标。目标1。阐明血小板的机制 mRNA被转移到癌细胞中。 AIM 2。确定癌细胞中血小板PF4 mRNA的转移 促进癌症转移。