Sox2 Cooperates with Lkb1 Loss in a Mouse Model of Squamous Cell Lung Cancer

•Lentiviral approach identifies combinatorial gene drivers in lung cancer•Sox2 expression and Lkb1 loss cooperate to promote lung squamous cell carcinoma•Mouse lung tumors recapitulate human SCC histology and biomarker expression•SCCs display activation of potential therapeutic targets FGFR2, STAT3, NF-κB, and mTOR

SummarySquamous cell carcinoma (SCC) of the lung is the second most common subtype of lung cancer. With limited treatment options, the 5-year survival rate of SCC is only 15%. Although genomic alterations in SCC have been characterized, identifying the alterations that drive SCC is critical for improving treatment strategies. Mouse models of SCC are currently limited. Using lentiviral delivery of Sox2 specifically to the mouse lung, we tested the ability of Sox2 to promote tumorigenesis in multiple tumor suppressor backgrounds. Expression of Sox2, frequently amplified in human SCC, specifically cooperates with loss of Lkb1 to promote squamous lung tumors. Mouse tumors exhibit characteristic histopathology and biomarker expression similar to human SCC. They also mimic human SCCs by activation of therapeutically relevant pathways including STAT and mTOR. This model may be utilized to test the contribution of additional driver alterations in SCC, as well as for preclinical drug discovery.

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