P45 Impaired autophagy signalling in cutaneous squamous cell carcinoma: a novel therapeutic target

Abstract Introduction and aims Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and the third most prevalent malignancy in the UK. Most cSCC arise from premalignant lesions called actinic keratosis (AK), but most AK will not develop into cSCC. While most cSCC are cured with surgical removal, a small proportion are high-risk and may progress to locoregional recurrence and metastatic cSCC, which has a poor prognosis. As many gene mutations identified in cSCC are also present in normal skin and AK, it is hard to differentiate what drives initial cSCC development, and subsequent progression. Investigating alterations in key cellular processes and pathways may reveal what drives these changes. Autophagy is a metabolic process essential for cell health, in which cellular waste is sequestered into specialized structures named autophagosomes and degraded. Analysis of RNA sequencing cSCC databases revealed a high mutational frequency in autophagy genes; therefore, we hypothesize that deregulation of autophagy may contribute to cSCC progression and could provide a novel therapeutic avenue. Methods Using a panel of well-characterized AK and cSCC cell lines derived from immunosuppressed and immunocompetent patients, autophagic activity was assessed by Western blot analysis (n = 3). Results The first cell line panel was derived from an immunosuppressed organ transplant recipient who presented with a premalignant lesion, followed by primary, recurrent and metastatic cSCC. Autophagy was revealed to be blocked in the premalignant cells, while intact in the primary, recurrent and metastatic cell lines. In contrast, analysis of two cell lines derived from an immunocompetent patient revealed that autophagy was blocked in cells derived from a primary tumour, while intact in metastatic cells. Conclusions These results reveal differences in autophagic activity between stages of cSCC progression, and immune status of patient-derived cell lines, supporting the hypothesis that defective autophagy may contribute to the progression of cSCC.