Exosomes in HNSCC Progression

外泌体在 HNSCC 进展中的作用

基本信息

批准号：
10614381
负责人：
Alissa M Weaver
金额：
$ 31.39万
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/10614381
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 Invaded Ligands Lipids Lymphangiogenesis 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 Recurrent tumor Role Signal Transduction Signaling Protein Site Stains Structure Testing Tissue Microarray Tissue Sample Tissue Stains Tissues Tumor Angiogenesis Tumor Promotion Tumor-Derived Work angiogenesis autocrine 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 synergism 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.

外泌体是小的细胞外囊泡（EV），这些囊泡是从多虫分泌的内体（MVE），最近已被公认为可以促进癌症转移。外泌体携带生物活性蛋白，脂质和核酸，是重要但很差的了解肿瘤微环境的组成部分。我们最近发现肌动蛋白丰富称为Invadopodia的侵入性结构是癌细胞中MVE的关键对接部位，导致增强的外泌体分泌。此外，我们发现关键的Invadodia调节器 Cortactin增强了MVE对接和外泌体分泌。值得注意的是，cortactin是基因扩增的并在许多癌症中过表达，尤其是在头部和颈部鳞状细胞中癌（HNSCC）。此外，HNSCC中的Cortactin过表达与患者生存率降低并增加转移。基于这些数据，我们假设 Cortactin的过表达驱动HNSCC的预后不良，因为它的关键作用促进外泌体分泌。此外，我们假设这是关键的外泌体货物与皮质素协同作用，促进肿瘤诱导的血管生成，淋巴管生成，和转移。具体而言，我们已经将Ephb-磷信号识别为关键的血管生成由HNSCC分泌的外泌体调节的轴。因此，我们提出了数字和外泌体的分子货物以协同的方式驱动侵略性HNSCC行为。我们将检验这些假设，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。