142 Keratinocyte p38α ablation reveals a context-dependent regulation of tumor initiation, tumor type specification, maintenance, and malignant progression in several models of mouse skin tumorigenesis

We recently showed that, in response to the topical DMBA/TPA carcinogenesis regimen applied to dorsal skin, mice with conditional keratinocyte-specific genetic ablation of p38α (p38α-cKO) formed well-differentiated sebaceous adenomas (SAs) harboring a signature activating Hras mutation, in addition to characteristic benign and malignant squamous tumors. Mutant mice exhibited a 4:1 ratio of sebaceous to squamous tumors, and about 50% of the SAs presented unusual localization in the ventral mutant skin. Additionally, keratinocyte p38α loss led to reduced growth of chemically-induced squamous cell carcinomas (SCCs). We now report that p38α depletion resulted in modulation of the expression levels of the signature genes of RAS transformation in v-rasHa-initiated keratinocytes, and reduced growth of squamous tumors generated from v-rasHa-transformed keratinocytes following orthotopic grafting onto nude mice. Notably, keratinocyte p38α loss did not significantly affect EGFR/ERK signaling in the absence and the presence of oncogenic v-rasHa, while a subset of SCC super-enhancer-associated genes was repressed in p38α-null v-rasHa-transformed keratinocytes relative to their wild-type (WT) counterparts. In response to the DMBA complete carcinogenesis regimen, p38α-cKO, but not WT control mice, formed both SAs, and aggressive sebaceous carcinomas with high frequency. Taken together, our results reveal novel context-dependent effects of keratinocyte p38α depletion on skin tumor formation.