448 RSPO1-mutated keratinocytes from palmoplantar keratoderma display impaired differentiation, alteration of cell-cell adhesion, EMT-like phenotype and invasiveness properties

Secreted R-spondin (RSPO) proteins play a key role in reproductive organ development, epithelial stem cell renewal and cancer induction by reinforcing canonical Wnt signaling. We have previously reported that palmoplantar keratoderma (PPK), predisposition to cutaneous squamous carcinoma (SCC) development sex reversal segregate as autosomal recessive trait patients carrying RSPO1-mutations. Although our previous findings suggested RSPO1 secreted from fibroblasts regulates keratinocyte growth or differentiation, the of this protein epidermis remains largely unexplored. Our study was aimed at expanding characterization RSPO1-mutated skin keratinocytes. Primary keratinocytes PPK patient displayed highly impaired differentiation EMT-like phenotype. Interestingly, expressed markers increased proliferation, dedifferentiation altered cell-cell adhesion. All these signs were more evident SCC specimens. patient’s exhibited expression ECM remodeling enzymes showed invasiveness properties an organotypic model presence fibroblasts, which behave like cancer-associated fibroblasts. Notably, induced hyperproliferative dedifferentiated phenotype control signaling has both promotion development. Accordingly, mediators differentially specimens compared control. data indicate absence affects microenvironment epidermal integrity, thus contributing risk tumorigenesis areas exposed major frictional stresses.