Exosomes in HNSCC Progression

外泌体在 HNSCC 进展中的作用

基本信息

批准号：
10341210
负责人：
Alissa M Weaver
金额：
$ 39.04万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10341210
关键词：
Actins Behavior Biological Markers Blood Body Fluids Cells Clinical Complement Data Defect Development Distant Metastasis Docking EMS1 gene Endosomes Ephrin B Receptor Ephrin-B2 Ephrins Family Flow Cytometry Gene Amplification Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Immunofluorescence Immunologic Lead Ligands Lipids Lymphangiogenesis Malignant Epithelial Cell Malignant Neoplasms Metastatic Neoplasm to Lymph Nodes Methods Modeling Molecular Neck Dissection Neoplasm Metastasis Nucleic Acids Oncogenic Pathologic Pathological Staging Patients Plasma Play Prognosis Proteins Proteomics Public Health Recurrence Role Signal Transduction Signaling Protein Site Small Cell Carcinoma Stains Structure Testing Tissue Microarray Tissue Sample Tissue Stains Tissues Tumor Angiogenesis Tumor Promotion Tumor-Derived Work angiogenesis autocrine base cancer cell cell motility combinatorial exosome extracellular vesicles genetic regulatory protein in vivo intercellular communication interest liquid biopsy lymph nodes member migration novel overexpression paracrine patient prognosis radiological imaging tumor tumor growth tumor microenvironment tumor progression

项目摘要

Exosomes are small extracellular vesicles (EVs) that are secreted from multivesicular endosomes (MVE) and have been recently recognized to promote cancer metastasis. Exosomes carry bioactive proteins, lipids and nucleic acids and are an important but poorly understood component of the tumor microenvironment. We recently discovered that actin-rich invasive structures called invadopodia are key docking sites for MVE in cancer cells, leading to enhanced exosome secretion. Furthermore, we found that the key invadopodia regulator cortactin enhances MVE docking and exosome secretion. Notably, cortactin is gene amplified and overexpressed in a number of cancers, especially in head and neck squamous cell carcinoma (HNSCC). Furthermore, cortactin overexpression in HNSCC is correlated with decreased patient survival and increased metastasis. Based on these data, we hypothesize that cortactin overexpression drives poor prognosis in HNSCC due to its key role in promoting exosome secretion. Furthermore, we hypothesize that key exosome cargoes synergize with cortactin to promote tumor-induced angiogenesis, lymphangiogenesis, and metastasis. Specifically, we have identified EphB-ephrinB signaling as a key angiogenic axis regulated by HNSCC-secreted exosomes. Thus, we propose that both the number and molecular cargo of exosomes drive aggressive HNSCC behavior in a synergistic manner. We will test these hypotheses and leverage our work to identify potential exosomal blood-and tissue-based biomarkers of regional and distant metastasis.

外泌体是由多囊泡分泌的小型细胞外囊泡（EV）内体（MVE）最近被认为可以促进癌症转移。外泌体携带生物活性蛋白质、脂质和核酸，是一种重要但作用较弱的物质。了解肿瘤微环境的组成部分。我们最近发现富含肌动蛋白称为侵袭伪足的侵袭性结构是癌细胞中 MVE 的关键对接位点，导致增强外泌体分泌。此外，我们发现关键的侵袭伪足调节因子 cortactin 增强 MVE 对接和外泌体分泌。值得注意的是，cortactin 是基因扩增的并在多种癌症中过度表达，尤其是在头颈鳞状细胞中癌（头颈部鳞癌）。此外，HNSCC 中 cortactin 的过度表达与患者生存率降低并增加转移。根据这些数据，我们假设 Cortactin 过度表达导致 HNSCC 预后不良，因为它在促进外泌体分泌。此外，我们假设关键的外泌体货物与 Cortactin 协同促进肿瘤诱导的血管生成、淋巴管生成、和转移。具体来说，我们已经确定 EphB-ephrinB 信号传导是关键的血管生成轴由 HNSCC 分泌的外泌体调节。因此，我们建议数量和外泌体的分子货物以协同方式驱动 HNSCC 的侵袭性行为。我们将测试这些假设并利用我们的工作来识别潜在的外泌体血液和区域和远处转移的基于组织的生物标志物。