Somatostatin receptor 4 ( SSTR4 ) is a tumor suppressor in cutaneous and head & neck squamous cell carcinomas

The mutational landscape of head & neck and cutaneous squamous cell carcinomas (HNSCC, cSCC) has major gene alterations involving PIK3CA , NOTCH1 , and TP53 among others that contribute to tumorigenesis. In this study, we focused on somatostatin receptor 4 ( SSTR4 ), which was identified in a recent in vivo HNSCC CRISPR screen. Mutations in the SSTR protein family are more commonly implicated in neuroendocrine tumors, and to date, no studies have shown a link between SSTR4 and cSCC/HNSCC. To understand the role of Sstr4 in skin keratinocytes, we employed transcriptomic profiling and proteomic methods and identified enriched pathways and protein–protein interactions (PPIs) networks. Sstr4 activation by J‐2156 agonist regulated MAPK‐ERK signaling pathway, which simultaneously limited G1 to S phase cell cycle progression. To validate Sstr4 as a driver of cSCC/HNSCC tumorigenesis, we performed a localized and clonal Sstr4 knockout in basal keratinocytes of the Pik3ca ^H1047R oncogenic mouse model using ultrasound‐guided in‐utero lentivirus injection technology. Tumor formation in mice following Sstr4 knockout occurred rapidly around 12 weeks. Our study is the first to uncover Sstr4 role in cSCC/HNSCC through in‐vivo models.