Abstract 334: PIK3CA overexpression induces epithelial-mesenchymal transition and progression of head and neck squamous cell carcinonoma.

Abstract

Abstract 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. Amplification and mutation of PIK3CA, the gene coding for the catalytic subunit of PI3K, are among the most common genetic alterations in human HNSCC. To delineate the in vivo roles of PIK3CA during head and neck tumorigenesis, we developed a PIK3CA genetically engineered mouse model (GEMM), in which PIK3CA overexpression is specifically induced in the head and neck epithelia. While overexpression of PIK3CA alone resulted in epithelial hyperplasia, and carcinoma in situ, it was not sufficient to induce visible tumor formation. In contrast, when we applied 4NQO, a DNA adduct-forming agent widely used as a tobacco surrogate together with PIK3CA overexpression, the PIK3CA-GEMM developed ∼50% poorly differentiated HNSCC compared to ∼10% of those in the control mice. PIK3CA tumors also had increased numbers of infiltrated leukocytes and angiogenesis. In addition, either regional lymph node metastases or lung metastases was observed in ∼40% of the PIK3CA-GEMM compared to no metastases in control mice. Characterizations of PIK3CA tumors revealed that PIK3CA tumors underwent epithelial and mesenchymal transition, and formed poorly differentiated metastatic tongue SCC in an orthotopical mouse model. Molecular analysis of the PIK3CA tumors suggests that rather than AKT, PDK1 facilitates progression of PI3K-driven HNSCC, and enhanced TGFbeta signaling with increased TGFbeta1 ligand and Smad3 may further contribute to this process. Lastly, overexpression of PIK3CA is associated with HNSCC progression and metastasis, and positively correlated with PDK1 expression but negatively with AKT activation, further verified the clinical relevance of our GEMM study. In summary, our results suggest that PIK3CA oncogene drives invasion and metastasis of HNSCC through PDK1 and TGFbeta signaling, and combined targeting of these pathways will reduce tumor progression in advanced HNSCC patients with PIK3CA alterations, which comprise about ∼40% of all HNSCC patients. Citation Format: Li Du, Xi Chen, Jingping Shen, Fang Zhang, Shi-Long Lu. PIK3CA overexpression induces epithelial-mesenchymal transition and progression of head and neck squamous cell carcinonoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 334. doi:10.1158/1538-7445.AM2013-334