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.
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.
|Du, L; Chen, X; Cao, Y et al. (2016) Overexpression of PIK3CA in murine head and neck epithelium drives tumor invasion and metastasis through PDK1 and enhanced TGF? signaling. Oncogene 35:4641-52|
|Malkoski, Stephen P; Cleaver, Timothy G; Thompson, Joshua J et al. (2014) Role of PTEN in basal cell derived lung carcinogenesis. Mol Carcinog 53:841-6|
|Frolova, Liliya V; Magedov, Igor V; Romero, Anntherese E et al. (2013) Exploring natural product chemistry and biology with multicomponent reactions. 5. Discovery of a novel tubulin-targeting scaffold derived from the rigidin family of marine alkaloids. J Med Chem 56:6886-900|
|White, Ruth A; Neiman, Jill M; Reddi, Anand et al. (2013) Epithelial stem cell mutations that promote squamous cell carcinoma metastasis. J Clin Invest 123:4390-404|
|Minor, Jacob; Wang, Xiaotian; Zhang, Fang et al. (2012) Methylation of microRNA-9 is a specific and sensitive biomarker for oral and oropharyngeal squamous cell carcinomas. Oral Oncol 48:73-8|
|Malkoski, Stephen P; Haeger, Sarah M; Cleaver, Timothy G et al. (2012) Loss of transforming growth factor beta type II receptor increases aggressive tumor behavior and reduces survival in lung adenocarcinoma and squamous cell carcinoma. Clin Cancer Res 18:2173-83|
|Du, Li; Shen, Jingping; Weems, Andrew et al. (2012) Role of phosphatidylinositol-3-kinase pathway in head and neck squamous cell carcinoma. J Oncol 2012:450179|
|Weber, Stephen M; Bornstein, Sophia; Li, Yuexin et al. (2011) Tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induces AKT activation in head and neck epithelia. Int J Oncol 39:1193-8|