RAS suppression of PAR3 and its effects on SCC initiation and tissue architecture occurs independently of hyperplasia

Abstract

Proper epithelial development and homeostasis depends on strict control of oriented cell division. Current evidence shows that this process is regulated by intrinsic polarity factors and external spacial cues. Due to the lack of appropriate model system that can recapitulate skin's architecture, deregulation of spindle orientation in human epithelial carcinoma has never been investigated. Using an inducible model of human squamous cell carcinoma (SCC), we demonstrate that RAS-dependent suppression of PAR3 accelerates epithelial disorganization during early tumorigenesis. Diminished PAR3 led to loss of E-cadherin mediated cell adhesion, which in turn contributed to misoriented cell division. Pharmacological inhibition of the MAPK pathway downstream of RAS activation reversed the defects in PAR3 expression, E-cadherin mediated cell adhesion and mitotic spindle orientation. Thus, temporal analysis of human neoplasia provides a powerful approach to study cellular and molecular transformations during early oncogenesis, which allowed identification of PAR3 as a critical regulator of tissue architecture during initial human SCC development.