Dysregulation of developmental transcription factor programs in Merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine (NE) carcinoma of the skin for which targeted therapeutic approaches and improved subtype classification are sorely needed. MCC is usually treated in a relatively standardized manner without consideration of subtype, which is currently defined by viral or nonviral etiology. Nonetheless, prior work on MCC and other NE carcinomas has indicated that non-etiological groups may exist which are better defined by transcription factor expression profiles, and that some of these groups may exhibit unique therapeutic vulnerabilities. I explore these ideas in two studies. In the first study, I show that developmental transcription factors with bivalent promoters are major contributors to MCC cell growth suppression by inhibitors of the repressive histone methyltransferase EZH2. Specifically, I utilize RNA-seq, CUT&RUN, a genome-wide CRISPR knockout screen, and a xenograft study to show that epigenetic derepression of the inner ear hair cell mechanosensory transcription factor SIX1 is a key determinant of EZH2 inhibitor-induced MCC growth suppression. In the second study, I identify novel MCC tumor groups defined by reciprocal expression of NE transcription factors and the Hippo pathway transcription factors YAP and TAZ. Furthermore, I show that YAP and TAZ are growth-suppressive when introduced into NE-hi, YAP/TAZ-lo MCC cells, and that WWTR1 (TAZ) can be derepressed in MCC cells by EZH2 inhibitors much like SIX1. In summary, this work reveals the previously unrecognized importance of MCC transcriptional profiles in defining both MCC subgroups and therapeutic vulnerabilities.