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）患者预后差，侵袭转移是死亡的主要原因。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）途径调节肿瘤发生的一系列关键细胞过程，PIK3CA扩增和突变是人类HNSCC中最常见的遗传改变之一。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尚未得到很好的描述。我们的初步研究表明，PIK3CA过表达与人类HNSCC的肿瘤进展呈正相关。小鼠口腔上皮中PIK3CA过表达通过增加肿瘤上皮细胞上皮间质转化和肿瘤间质血管生成和炎症增加肿瘤侵袭性和转移。这些肿瘤的初步分子分析表明，PDK1而不是AKT促进了pi3k驱动的HNSCC的进展，而TGFb信号的增强可能进一步促进了这一过程。我们假设PI3K通路通过PDK1和TGF？这些途径的联合靶向将减少PIK3CA改变的晚期HNSCC患者的肿瘤进展。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TGF？信号传导有助于PI3K驱动的HNSCC进展。3)利用PI3K和TGF?优化治疗策略抑制HNSCC进展。本研究不仅将对PI3K通路如何驱动HNSCC侵袭转移提供重要的见解，而且将转化为针对PI3K和TGF？PIK3CA改变的晚期HNSCC患者

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.