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中起重要作用。 了解血小板如何与癌细胞通讯以调节癌细胞在远处的定植 器官可能会发现阻止癌症扩散的新策略。我们最近发现，血小板的募集， 癌细胞对于循环肿瘤细胞（CTC）在次级器官的定殖是必需的。然而，在这方面， 血小板调节癌细胞功能以促进癌细胞定植的分子机制 还有待确定。通过分析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中显著富集。RNAscope和翻译核糖体亲和纯化 （TRAP）分析显示了血小板mRNA的递送和血小板衍生的mRNA在癌细胞中的翻译。 体内功能筛选鉴定多种血小板源性mRNA有助于乳腺癌的定植 细胞在远处的器官。这些结果揭示了血小板mRNA在介导细胞间 沟通和促进癌细胞扩散。本提案的总体目标是界定 血小板mRNA进入乳腺癌细胞并决定血小板作用的分子机制 mRNA作为促进癌细胞在远处器官定植的信号分子。我们发现CD 9 CTC中的表达与血小板特异性mRNA的积累相关。沉默乳腺癌中的CD 9 细胞显著减少血小板mRNA的转移和癌细胞的定植。血小板因子4（PF 4） 一种属于CXC趋化因子家族的小细胞因子，在血小板中高度表达。我们发现 从血小板向乳腺癌细胞转移PF 4 mRNA增强了癌症的干细胞性和定殖 细胞基于这些结果，该提议的中心假设是CD 9依赖性mRNA转移 介导血小板-癌细胞通讯并促进癌细胞的干细胞性。我们提议下列 两个目的是检验这一假设并实现我们的目标。目标1。阐明了血小板 mRNA被转移到癌细胞中。目标二。确定血小板PF 4 mRNA如何在癌细胞中转移 促进癌症转移。