Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression

The systematic identification of genetic events driving cellular transformation and tumor progression in the absence of a highly recurrent oncogenic driver mutation is a challenge in cutaneous oncology. In cutaneous squamous cell carcinoma (cuSCC), the high UV-induced mutational burden poses a hurdle to achieve a complete molecular landscape of this disease. Here, we utilized the transposon mutagenesis system to statistically define drivers of keratinocyte transformation and cuSCC progression in the absence of UV-IR, and identified established tumor suppressor genes, as well as previously unknown oncogenic drivers of cuSCC. Functional analysis confirms an oncogenic role for the genes, and tumor suppressive roles for and , in the initiation or progression of human cuSCC. Taken together, our screen demonstrates an extremely heterogeneous genetic landscape of cuSCC initiation and progression, which could be harnessed to better understand skin oncogenic etiology and prioritize therapeutic candidates.