The Development and Progression of Mouse Oral Squamous Cell Carcinoma is Associated with Mutations in Cell Adhesion and Development

To investigate the carcinogenesis steps that lead to oral squamous cell carcinoma (OSCC) we performed lineage tracing in K14-CreERTAM; Rosa26LacZ mice treated with the tobacco surrogate, the carcinogen 4-nitroquinoline-1-oxide (4-NQO). Our group and others have demonstrated that the tongue tumors developing after 4-NQO treatment recapitulate some aspects of human OSCCs but it is still unclear which cells of the tongue epithelium contribute to carcinogenesis and what is the mutational profile at different steps of carcinogenesis. By laser capture microdissection we isolated the clonal cell populations from long-term epithelial stem cells LacZ+ in pre-neoplastic and fully formed SCCs and performed whole exome sequencing. For this study we included three mice that received no carcinogen and used them as controls, and eight mice treated with the carcinogen for 10 weeks. Among the 4-NQO-treated mice, we sacrificed 3 mice with no tumors after the 10 weeks of treatment (pre-neoplastic samples), whereas the remaining 5 mice developed SCC in the tongue epithelium 17 to 27 weeks after the end of the 4-NQO treatment (tumor samples). The finding from this work shed light on the mutational changes occurring before tumor formation and in frank OSCC, and establishes the role of the clonal cell populations from long-term epithelial stem cells LacZ+ in these tumors.