Squamous cell carcinomas (SCCs) are a group of tumors with shared molecular features across organ types, few targeted treatments, and poorly defined drivers of carcinogenesis. We explored the possibility that alternative RNA splicing is a fundamental mechanism of carcinogenesis across SCC types. Exploiting large scale transcriptional profiling data, we found that splicing profiles significantly differ between SCC and non-SCC cell lines and identified an SCC-specific splicing signature which was characterized by retained intron, exon skipping, and isoform-level events associated with pathways of tumor growth, invasion and metastasis. PCA-based cluster analysis showed that splicing changes between SCCs and non-SCCs are driven by dysregulation of splicing factor abundance and unrelated to mutations in splicing factors, cancer driver genes or markers of squamous differentiation. The splicing-regulatory network built using motif enrichment and protein network data revealed SRSF10 to be a major regulator of oncogenic splicing in SCC. Validation of our results with TCGA and GTEx data confirmed many pan-SCC retained intron and exon skipping events and supported the role of alternative splicing in regulating survival- and cancer-related genetic programs in SCC. In summary, we show that splicing dysregulation in SCCs is not a mere passenger phenomenon, but likely constitutes a critical driver of oncogenesis. This suggests that targeting core splicing modulators, such as SRSF10, might be a viable therapeutic strategy to treat SCCs.

ESDR482 - Squamous Cell Carcinoma – A Splicing Disease

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.