Investigation of the Role of Chromosome 3q26-28 Amplification in Lung Squamous Cell Carcinoma Pathogenesis

Lung cancer is the leading cause of cancer mortality with squamous cell carcinoma (SQCC) being the second most common form. Lung SQCCs likely originate from basal cells, the stem cells in the bronchial epithelium. Although these cells are normally quiescent and differentiate into ciliated and mucinous progeny, smoking triggers an injury response leading to basal cell hyperplasia and squamous metaplasia, which appears to wane over time as most metaplasias regress, even with continued smoking. However, some metaplasias fail to regress and progress to dysplasia and SQCC through unknown mechanisms. Using primary human tracheobronchial basal cells, we investigated how copy number gains in SOX2 at 3q26-28, which are observed in 94% of SQCCs commencing in dysplasia, promote SQCC progression. We find that SOX2 levels normally oscillate in basal cells, with transient low expression required for ciliated cell differentiation and subsequent increase in SOX2 levels driving mucinous differentiation. By contrast, during injury that promotes squamous metaplasia, PI3K signaling is activated and cooperates with SOX2 to instruct basal cells to enter the hyperproliferative and squamous-committed state, with additional coregulation by TP63, and EP300. We propose that smoking initially induces an unstable metaplastic injury state that creates fields of proliferating stem cells, with coamplification of SOX2, PIK3CA and TP63 at 3q26-28 stabilizing this state and preventing return to a quiescent state. Finally, we provide evidence for PI3K and EP300 inhibitors as chemopreventatives, and their combination as a novel therapeutic strategy to treat SQCCs.Ph.D