The directionality of collective cell delamination is governed by tissue architecture and cell adhesion in a Drosophila carcinoma model

Abstract

Carcinomas originate in epithelia and are the most frequent type of cancers. Tumor progression starts with the collective delamination of live tumors out of the epithelium, and requires modulation of cell adhesion. Yet, it remains elusive exactly how remodeling of epithelial cell-cell and cell-extracellular matrix contacts contribute to metastasis onset and delamination directionality. We used Drosophila melanogaster larval eye disc to study cooperative oncogenesis and determine the contribution of bi- and tricellular septate junction (SJ) components to tumor progression in flat and pseudostratified epithelia. We reveal that loss-of-function of septate junction components alone can promote cell death whereas synergic interaction with oncogenic Ras triggers the collective delamination of living tumorigenic cells. Spatiotemporal analyses reveal apical and basal delamination processes differ in terms of cell identity, cell polarity and remodeling of cell-cell and cell-ECM contacts. Using a combination of in vivo and in silico approaches, we report that SJ-depleted RasV12 tumors in pseudostratified epithelia trigger tissue folding or basal collective delamination regardless of the order in which cell contacts are remodeled. In striking contrast, SJ-depleted RasV12 tumors formed in flat, squamous epithelia, first undergo apical constriction and acquire a dome-like shape. Tumors are enriched in adhesion molecules and form an apical neck at the interface of contact between mutant cells and wild-type neighbors. Concomitant to cytoskeleton remodeling, tumors emit apical protrusions in the lumen and progressively delaminate through the apical neck while remaining cohesive. Our study reveals that tissue architecture and changes in cell adhesion drive the directionality of collective delamination of neoplastic tumors out of an epithelium.