Author:
Halaoui Ruba,Rejon Carlis,Chatterjee Sudipa June,Szymborski Joseph,Meterissian Sarkis,Muller William J.,Omeroglu Atilla,McCaffrey Luke
Abstract
Epithelial cancers (carcinoma) account for 80%–90% of all cancers. The development of carcinoma is associated with disrupted epithelial organization and solid ductal structures. The mechanisms underlying the morphological development of carcinoma are poorly understood, but it is thought that loss of cell polarity is an early event. Here we report the characterization of the development of human breast lesions leading to carcinoma. We identified a unique mechanism that generates solid ducts in carcinoma through progressive loss of polarity and collapse of the luminal architecture. This program initiates with asymmetric divisions of polarized cells that generate a stratified epithelium containing both polarized and depolarized cells. Stratified regions form cords that penetrate into the lumen, subdividing it into polarized secondary lumina. The secondary lumina then collapse with a concomitant decrease in RhoA and myosin II activity at the apical membrane and ultimately lose apical–basal polarity. By restoring RhoA activity in mice, ducts maintained lumen and cell polarity. Notably, disrupted tissue architecture through luminal collapse was reversible, and ducts with a lumen were re-established after oncogene suppression in vivo. This reveals a novel and common mechanism that contributes to carcinoma development by progressively disrupting cell and tissue organization.
Funder
Fonds Recherche du Quebec-Santé
Defi Canderel and Karassik Family Foundation
Fonds Recherche du Quebec-Santé Research
Komen Career Catalyst
Cancer Research Society
Quebec Breast Cancer Foundation
Canada Foundation for Innovation
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
43 articles.
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