Epithelial Tissue Architecture Acts as a Barrier to Carcinoma Initiation

Here, we identify epithelial architectural homeostasis as a critical barrier to oncogene-induced disorganization and carcinoma initiation. Using inducible KRASG12V and ERBB2 expression in Caco2 epithelial cysts, we demonstrate that proliferation alone is insufficient to disrupt tissue organization.

Instead, epithelial disorganization arises from impaired resolution of misoriented cell divisions, apical budging, and lumen collapse, processes exacerbated by KRASG12V but not ERBB2. We show that tight junction integrity is essential to maintain monolayer architecture, and that its disruption enables ERBB2-induced disorganization. Oncogene dosage further modulates architectural disruption severity, with high KRAS expression driving lumen collapse and loss of polarity.