Regulation of extracellular vesicle biogenesis through cell adhesion

通过细胞粘附调节细胞外囊泡生物发生

• 批准号: 10652271
• 负责人: Heather H Pua
• 金额: $ 54.79万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-06 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652271
• 关键词: Activated-Leukocyte Cell Adhesion Molecule; Adhesions; Autocrine Communication; Back; Behavior; Biogenesis; Biological; Biological Process; Biology; Bladder Urothelium; Cadherins; Cancer Patient; Cancer cell line; Cell Adhesion; Cell Line; Cell-Cell Adhesion; Cells; Cessation of life; Chemicals; Clinical; Coculture Techniques; Companions; Complex; Cytoplasm; DNA; Disease Progression; Equilibrium; Event; Exhibits; Human; Immunoglobulin G; Integrins; Intervention; Invaded; Knockout Mice; Laboratories; Laboratory Study; Length; Letters; Link; Lipids; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mass Spectrum Analysis; Mediating; Mediator; Modeling; Molecular; Neoplasm Metastasis; Papilloma; Paracrine Communication; Pathway interactions; Phenotype; Primary Neoplasm; Process; Production; Protein Isoforms; Proteins; Proteomics; Publishing; RNA; RNA Splicing; Regulation; Reproducibility; Resistance; Retrospective cohort; Scaffolding Protein; Structure; System; Testing; Tumor-Derived; Urine; Validation; Variant; Vesicle; Work; adhesion receptor; bladder Carcinoma; cancer cell; cell motility; clinical phenotype; clinically significant; experimental study; extracellular vesicles; imaging probe; innovation; member; mouse model; neoplastic cell; novel; paracrine; prognostic indicator; response; success; survival prediction; synergism; tumor; tumor progression; vesicular release

Abstract Metastasis is a well-known driver of cancer-related deaths. Nevertheless, limited success has been achieved in targeting cancer metastasis because it is an exceedingly complex process driven by multiple, integrated mechanisms. Collaborative studies in the Zijlstra and Weaver laboratories studied two separate aspects of cell motility: a) the dynamics of cell-cell adhesion controlled by proteolytic shedding of adhesion receptor and b) the release of motility promoting extracellular vesicles (EV). Since these two events take place in the same cells and contributed to the same phenotype, we speculated that these two biological processes were coordinated. Indeed, preliminary studies demonstrated that syntenin-1, a key component of the EV biogenesis pathways, was part of a cell adhesion complex anchored by the IgG superfamily member Activated Leukocyte Cell Adhesion Molecule (ALCAM) and its companion-tetraspanin CD151. Altering the expression and/or shedding of ALCAM drastically impacted EV biogenesis, confirming our original idea that cell-cell adhesion could be coordinated with EV biogenesis. The hypothesis that this occurred through an intracellular link between ALCAM and syntenin is further supported by the ability of free intracellular domain to suppress EV biogenesis. Based on these observations and our published expertise in cell adhesion, EV biology and metastasis, we propose to investigate the integration between cell-adhesion and the production of motility-promoting EVs during cancer progression. Specifically, the proposed studies will investigate: 1) the mechanistic integration between cell-adhesion and EV biogenesis, 2) the consequences for cargo incorporated in motility-promoting EVs, and 3) the functional contribution to autocrine and paracrine communication. Moreover, the relevance of this biology will be tested in the context of bladder cancer where ALCAM shedding is an independent prognostic indicator of survival. For this purpose we have developed a novel ex vivo organotypic culture system for bladder urothelium and bladder cancer in which we can replicate the clinical phenotypes of both papilloma and carcinoma of the bladder. Considering that tumor cells have a large number of divergent mechanisms at their disposal by which they can enhance their malignant behavior, determining how mechanisms of cell adhesion and EV biogenesis integrate is not only an innovative way to deconvolve complex metastatic behavior, it will also have significant clinical impact. With findings from the propose studies, will provide novel avenues of intervention where a therapy may target a point of synergy and integration rather than a direct mode of action.

抽象的 转移是与癌症相关死亡的著名驱动因素。然而，在 靶向癌症转移，因为它是一个非常复杂的过程，由多个集成 机制。 Zijlstra和Weaver Laboratories的合作研究研究了细胞的两个独立方面 运动：a）通过粘附受体的蛋白水解脱落控制的细胞细胞粘附动力学和b） 释放促进细胞外囊泡的运动性（EV）。由于这两个事件发生在相同的单元格中，并且 我们促进了相同的表型，我们推测这两个生物学过程是协调的。的确， 初步研究表明，syntenin-1是EV生物发生途径的关键组成部分，是 由IgG超家族成员激活的白细胞粘附分子锚定的细胞粘附复合物 （ALCAM）及其伴随四叠素CD151。大大改变Alcam的表达和/或脱落 受影响的EV生物发生，证实了我们最初的观念，即细胞细胞粘附可以与EV协调 生物发生。通过Alcam和Syntenin之间的细胞内联系发生的假设是 自由细胞内结构域抑制EV生物发生的能力进一步支持。基于这些 观察以及我们在细胞粘附，EV生物学和转移方面发表的专业知识，我们建议调查 细胞粘附与癌症进展过程中促进性电动汽车的产生之间的整合。 具体而言，拟议的研究将研究：1）细胞粘附与EV之间的机械整合 生物发生，2）纳入运动性EV中的货物的后果，3）功能 对自分泌和旁分泌交流的贡献。此外，该生物学的相关性将在 Alcam脱落是生存的独立预后指标的膀胱癌的背景。为了 这个目的，我们开发了一种新型的体内器官型培养系统，用于膀胱尿皮细胞和膀胱 我们可以在其中复制乳头瘤和膀胱癌的临床表型。 考虑到肿瘤细胞具有大量不同的机制，可以通过它们 增强其恶性行为，确定细胞粘附和EV生物发生的机制如何整合 不仅是变形复杂转移行为的创新方式，还将具有重要的临床 影响。通过提出研究的发现，将提供新的干预途径 针对协同和集成的点，而不是直接的作用方式。