Open AccessRAS suppression of PAR3 and its effects on SCC initiation and tissue architecture occurs independently of hyperplasia
Author(s) -
Ling Ji,
Maria Sckaff,
Manisha Tiwari,
Yifang Chen,
Jingting Li,
Jackson Jones,
George L. Sen
Publication year - 2020
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.249102
Subject(s) - biology , microbiology and biotechnology , carcinogenesis , cell division , cdc42 , cadherin , cell growth , mitosis , regulator , cell polarity , cell , cell adhesion , cancer research , cancer , signal transduction , genetics , gene
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.