Depicting CREB-Dependent Transcriptome in MCPyV+ and MCPyV- Merkel Cell Carcinoma Cells

Abstract

Merkel Cell Carcinoma (MCC) is a highly malignant neuroendocrine tumor with an increasing incidence and the highest mortality rate amongst skin cancers (30%). They are usually diagnosed at advanced stages and still lack precise markers for diagnosis. MCC has two main etiologies: polyomavirus-positive (MCPyV+) and -negative (MCPyV-). MCPyV+ harbour integrated copies of viral DNA and low mutational index (MI <1) accounting for 50- 80% of the MCC. MCPyV- display a high MI (>10), with a UV-mutational signature (60% C>T and 5% CC>TT). Treatments are based on surgery with adjuvant radiotherapy or chemotherapy, but MCCs still lack targeted therapies. Importantly, MCCs show up to 70% of ORR to immune-checkpoint inhibitors, independently of the tumor etiology. CREB is a transcription factor activated by AC-cAMP-PKA. In MCC, CREB is highly deregulated and constitutes a malignant mechanism shared between MCPyV+ and MCPyV- tumors (HR=6 in both). Here, CREB-mediated transcriptome analysis has been performed using forskolin (a natural AC activator) under normal or deficient CREB activities in MCPyV+ (using a pharmacological CREB inhibitor) and in MCPyV- cells (CREB knocked-down). Data show specific transcriptomes in response to forskolin under normal and impaired CREB contexts. Furthermore, we show and analyze genes commonly CREB-regulated, between MCPyV+ and MCPyV- cellular backgrounds and provide independent validation. These CREB-target genes could help to explain the malignant mechanisms driving MCCs from any etiology, and could lead to set-up specific molecular approaches for the diagnosis, develop novel targeted therapies or predict responses to immunotherapy.