AR facilitates YAP-TEAD interaction with the AM promoter to enhance mast cell infiltration into cutaneous neurofibroma

Abundant mast cell infiltration and disease initiation at puberty are hallmark features of cutaneous neurofibroma (cNF). However, the association between mast cell infiltration and steroid hormones in cNF remains unclear. Here, we determined that androgen receptor (AR) expression is positively associated with mast cell density in cNF tissues. Moreover, both in vitro cell experiments and in vivo mouse models verified that activated AR promoted mast cell infiltration and that AR inhibition reduced mast cell infiltration. Analyses in cell models and xenograft tumours both demonstrated that AR upregulated Yes associate protein 1 (YAP)-adrenomedullin (AM) signalling. Clinical samples from cNF patients further verified that AR was positively related to YAP and AM. Mechanistic analysis revealed that AR accelerates AM transcription via enhancing YAP- TEA domain transcription factor (TEAD) binding to the AM promoter. Consequently, the upregulated AM enhanced mast cell recruitment. Interruption of the YAP-TEAD interaction or inhibition of AM could impair mast cell accumulation induced by active AR, which indicated that this newly found signalling pathway may provide novel targets for cNF treatment.