The Role of PI3K Pathway in Head and Neck Cancer Invasion and Metastasis

描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)患者预后较差，侵袭和转移是导致死亡的主要原因。然而，HNSCC侵袭和转移的分子机制尚不清楚。磷脂酰肌醇3-激酶(PI3K)通路调节肿瘤发生中至关重要的一系列细胞过程，而PIK3CA扩增和突变是人类HNSCC中最常见的基因改变之一。与PI3K通路在细胞生长和存活中的作用相比，PI3K通路在肿瘤侵袭和转移中的作用还没有被很好地阐明。我们的初步研究表明，PIK3CA的过度表达与人HNSCC的肿瘤进展呈正相关。PIK3CA在小鼠口腔上皮细胞中的过表达通过增加肿瘤上皮细胞上皮-间充质转化、肿瘤间质中血管生成和炎症来增加肿瘤的侵袭和转移。对这些肿瘤的初步分子分析表明，PDK1促进了PI3K驱动的HNSCC的进展，而不是AKT，而增强的TGFb信号可能进一步促进了这一过程。我们推测PI3K通路可能通过PDK1和转化生长因子？PIK3CA改变的晚期HNSCC患者中，信号转导和联合靶向这些通路将减少肿瘤进展。我们的具体目标是：1)确定PI3K/PDK1轴在HNSCC进展中的作用。2)如何确定转化生长因子？信号转导参与了PI3K驱动的HNSCC的进展。3)使用PI3K和转化生长因子优化治疗策略？抑制HNSCC进展的药物。这一建议不仅将为PI3K通路如何驱动HNSCC的侵袭和转移提供重要的见解，而且还将转化为针对PI3K和转化生长因子的临床应用？治疗晚期HNSCC患者PIK3CA改变的途径。 公共卫生相关性：这项提案将使用最先进的小鼠模型和实验方法来确定头颈部癌症侵袭和转移的分子机制。拟议的研究将导致识别生物标记物和治疗靶点，这些标记物和治疗靶点将直接转化为治疗头颈癌患者的临床应用。

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) patients have a poor prognosis and invasion and metastasis are the major causes of mortality. However, the molecular mechanisms of HNSCC invasion and metastasis remain obscure. The phosphatidylinositol 3-kinase (PI3K) pathway regulates a wide range of cellular processes crucial for tumorigenesis, and PIK3CA amplification and mutation are among the most common genetic alterations in human HNSCC. Compared to the well-documented roles of the PI3K pathway in cell growth and survival, the roles of PI3K pathway in tumor invasion and metastasis have not been well delineated. Our preliminary studies show that PIK3CA overexpression positively correlates with tumor progression in human HNSCC. PIK3CA overexpression in mouse oral epithelium increases tumor invasiveness and metastasis by increasing epithelial-mesenchymal transition in tumor epithelial cells, and angiogenesis and inflammation in tumor stroma. Preliminary molecular analysis of these tumors suggests that rather than AKT, PDK1 facilitates progression of PI3K-driven HNSCC, and enhanced TGFb signaling may further contribute to this process. We hypothesize that PI3K pathway drives invasion and metastasis of HNSCC through PDK1 and TGF? signaling, and combined targeting of these pathways will reduce tumor progression in advanced HNSCC patients with PIK3CA alterations. Our specific aims are: 1) Determine the role of the PI3K/PDK1 axis in HNSCC progression. 2) Determine how TGF? signaling contributes to PI3K- driven HNSCC progression. 3) Optimize therapeutic strategies using PI3K and TGF? inhibitors to control HNSCC progression. This proposal will not only provide significant insights into how PI3K pathway drives HNSCC invasion and metastasis, but will also translate into clinical applications targeting PI3K and TGF? pathway to treat advanced HNSCC patients with PIK3CA alterations. PUBLIC HEALTH RELEVANCE: This proposal will use state-of-the-art mouse models and experimental approaches to identify the molecular mechanisms underlying head and neck cancer invasion and metastasis. The proposed studies will lead to identification of biomarkers and therapeutic targets that will be directly translated into clinical applications for treating head and neck cancer patients.