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发挥着重要作用。 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 器官可能会找出阻止癌症扩散的新策略。我们最近表明，血小板的招募 癌细胞对于循环肿瘤细胞（CTC）在次要器官的定植至关重要。然而， 血小板调节癌细胞功能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 CTC 中特异性 mRNA 显着富集。 RNAscope 和翻译核糖体亲和纯化 (TRAP) 分析显示癌细胞中血小板 mRNA 的传递和血小板衍生 mRNA 的翻译。 体内功能筛选发现多种血小板衍生的 mRNA 有助于乳腺癌定植 远处器官的细胞。这些结果揭示了血小板 mRNA 在介导细胞间相互作用中的新作用。 沟通和促进癌细胞扩散。该提案的总体目标是定义 血小板 mRNA 被递送至乳腺癌细胞并决定血小板作用的分子机制 mRNA 作为信号分子促进癌细胞在远处器官定植。我们证明了 CD9 CTC 中的表达与血小板特异性 mRNA 的积累相关。沉默乳腺癌中的 CD9 细胞显着减少血小板 mRNA 转移和癌细胞定植。血小板因子 4 (PF4) 是 属于 CXC 趋化因子家族的一种小细胞因子，在血小板中高度表达。我们证明了 PF4 mRNA 从血小板转移到乳腺癌细胞增强了癌症的干细胞性和定植 细胞。基于这些结果，该提案的中心假设是 CD9 依赖性 mRNA 转移 介导血小板-癌细胞通讯并促进癌细胞干性。我们提出以下建议 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 mRNA 被转移到癌细胞中。目标 2. 确定血小板 PF4 mRNA 在癌细胞中的转移方式 促进癌症转移。