KRas-transformed epithelia cells invade and partially dedifferentiate by basal cell extrusion

Abstract

Metastasis is the main cause of carcinoma-related death, yet we know little about how it initiates due to our inability to visualize stochastic invasion events. Classical models suggest that cells accumulate mutations that first drive formation of a primary mass, and then downregulate epithelia-specific genes to cause invasion and metastasis. Here, using transparent zebrafish epidermis to model simple epithelia, we can directly image invasion. We find that KRas-transformation, implicated in early carcinogenesis steps, directly drives cell invasion by hijacking a process epithelia normally use to promote death—cell extrusion. Cells invading by basal cell extrusion simultaneously pinch off their apical epithelial determinants, endowing new plasticity. Following invasion, cells divide, enter the bloodstream, and differentiate into stromal, neuronal-like, and other cell types. Yet, only invading KRasV12 cells deficient in p53 survive and form internal masses. Together, we demonstrate that KRas-transformation alone causes cell invasion and partial dedifferentiation, independently of mass formation.

Tissue architecture in tumor initiation and progression

“…Although apical cell extrusion is a defense mechanism of epithelia, transformed cells can hijack this mechanism to facilitate invasion. In zebrafish epidermis KRAS V12 mutation induces basal extrusion, facilitating invasion beyond the epithelium [54].…”

Bilateral JNK activation is a hallmark of interface contractility and promotes elimination of aberrant cells

“…Importantly, oncogenic Ras is a potent suppressor of apoptosis in flies and mammalian tissues [73]. While this prevents elimination of these cells from imaginal discs, these cells are eliminated from mammalian tissue, however importantly: by a cell death independent mechanism that involves strong activation of interfacial actomyosin activity, driving mechanical squeezing out of the tissue layer [68][69][70][74][75][76][77][78]. We thus suggest that interface contractility and EDAC are evolutionarily conserved expression of the same ancient tissue-intrinsic defence system that specifically acts against cell fate deregulation.…”

LncRNA PCGEM1 in Human Cancers: Functions, Mechanisms and Promising Clinical Utility

“…Metastasis is the dominant cause of advanced tumor stage (66), and enhanced cell invasion and migration and PCGEM1 overexpression have been observed in diverse cancer cell lines. Zhang et al ( 43) revealed that PCGEM1 facilitates GC cell invasion and metastasis via the miR-129-5p/prolyl 4-hydroxylase subunit alpha 2 (P4HA2) axis (43).…”

“…Metastasis is the dominant cause of advanced tumor stage ( 66 ), and enhanced cell invasion and migration and PCGEM1 overexpression have been observed in diverse cancer cell lines. Zhang et al.…”