Podoplanin-positive carcinoma-associated fibroblasts drive progression and metastatic potential of head and neck squamous cell carcinoma

项目概要/摘要： 头颈部鳞状细胞癌是全球第六大常见恶性肿瘤。转移降低生存率 患者的发病率仅为37%，表明晚期疾病的严重程度，但仍有许多问题需要了解。 转移过程。新出现的证据表明肿瘤微环境有助于HNSCC进展， 该建议旨在阐明一种微环境细胞类型，癌相关成纤维细胞（CAF）的作用。 HNSCC具有向淋巴结转移的高倾向，相关研究表明HNSCC高表达， 跨膜糖蛋白podoplanin（PDPN）是患者预后差的指示。有人建议 CAF可能在淋巴结中表达PDPN，尽管这尚未确定。此外，PDPN+ CAF 其他癌症类型在促进或抑制癌症进展方面具有不同的作用， HNSCC的数据很少。这个项目将扩大我的初步数据表明CAF从两个主要的 肿瘤和肿瘤相关淋巴结确实是PDPN+，并加速体外HNSCC迁移。总体 目的是确定PDPN+ CAF促进HNSCC侵袭和迁移潜力的机制， 转移潜力的指标，以及评估PDPN+ CAF增强淋巴管生成和接种的能力。 淋巴结中的转移前、免疫抑制、肿瘤支持性小生境。体外分析将研究 可能影响HNSCC进展以及PDPN下游信号传导的PDPN依赖性分泌因子 在CAF内，这可能导致细胞收缩性和免疫抑制能力增加。所有体外数据将 在存在和不存在PDPN表达的情况下进行小鼠研究，结果分析淋巴结 脉管系统密度、淋巴结免疫浸润和总体转移性肿瘤负荷。研究结果预计将 鉴定PDPN和/或其效应物作为治疗转移性HNSCC的潜在靶标，以努力减少 死亡率由转移发生的破坏引起。

Project Summary/Abstract: Head and neck squamous cell carcinoma is the sixth most common malignancy worldwide. Metastasis reduces survival rates for patients to only 37%, indicating the severity of advanced disease, but there remains much to be understood about the metastatic process. Emerging evidence suggests the tumor microenvironment contributes to HNSCC progression and this proposal aims to clarify the role of one microenvironment cell type, carcinoma-associated fibroblasts (CAFs). HNSCC has a high propensity for metastasis to the lymph nodes, and correlative studies have indicated high expression of the transmembrane glycoprotein podoplanin (PDPN) is indicative of poor patient prognosis. It has been suggested that CAFs may be expressing PDPN in the lymph nodes, though this has yet to be determined. In addition, PDPN+ CAFs in other cancer types have been shown to have varying roles in either promoting or inhibiting cancer progression though little data exists for HNSCC. This project will expand upon my preliminary data indicating CAFs from both the primary tumor and tumor-associated lymph nodes are, indeed, PDPN+ and accelerate HNSCC migration in vitro. The overarching objectives are to identify the mechanism of PDPN+ CAFs in facilitating HNSCC invasive and migratory potential, as metrics of metastatic potential, as well as assess the ability of the PDPN+ CAFs to enhance lymphangiogenesis and to seed a pre-metastatic, immunosuppressed, tumor-supportive niche in the lymph nodes. In vitro analyses will investigate the PDPN-dependent secreted factors that may influence HNSCC progression as well as downstream signaling of PDPN within the CAFs that may result in increased cell contractility and immunosuppressive abilities. All in vitro data will be complemented by mouse studies in the presence and absence of PDPN expression with outcomes analyzing lymphatic vasculature density, lymph node immune infiltration, and overall metastatic tumor burden. Study findings are expected to identify PDPN and/or its effectors as (a) potential target(s) for the treatment of metastatic HNSCC in an effort to reduce mortality rates caused by the devastation of metastatic occurrence.