Abstract
Centrosome aberrations disrupt tissue architecture and may confer invasive properties to cancer cells. Here we show that structural centrosome aberrations, induced by overexpression of either Ninein-like protein (NLP) or CEP131/AZI1, sensitize polarized mammalian epithelia to basal cell extrusion. While unperturbed epithelia typically dispose of damaged cells through apical dissemination into luminal cavities, certain oncogenic mutations cause a switch in directionality towards basal cell extrusion, raising the potential for metastatic cell dissemination. Here we report that NLP-induced centrosome aberrations trigger the preferential extrusion of damaged cells towards the basal surface of epithelial monolayers. This switch in directionality from apical to basal dissemination coincides with a profound reorganization of the microtubule cytoskeleton, which in turn prevents the contractile ring repositioning that is required to support extrusion towards the apical surface. While the basal extrusion of cells harbouring NLP-induced centrosome aberrations requires exogenously induced cell damage, structural centrosome aberrations induced by excess CEP131 trigger the spontaneous dissemination of dying cells towards the basal surface from MDCK cysts. Thus, similar to oncogenic mutations, structural centrosome aberrations can favour basal extrusion of damaged cells from polarized epithelia. Assuming that additional mutations may promote cell survival, this process could sensitize epithelia to disseminate potentially metastatic cells.
Highlights
Centrosomes are the major microtubule (MT) organizing centres in animal cells and typically comprise two centrioles embedded in a pericentriolar matrix (PCM) [1,2,3,4,5]
The structural centrosome aberrations induced by excess Ninein-like protein (NLP) or CEP131 display distinct properties, we found that both types of aberrations influence the directionality of extrusion of damaged cells from epithelia
In consideration of the potential importance of basal cell extrusion for metastasis [28,29], this led us to ask whether NLP-induced centrosome aberrations might affect the directionality of extrusion of dying cells
Summary
Centrosomes are the major microtubule (MT) organizing centres in animal cells and typically comprise two centrioles embedded in a pericentriolar matrix (PCM) [1,2,3,4,5]. Experimental manipulation of centrosome numbers can trigger tumorigenesis in flies [12] as well as mice [13,14,15] This raises the question of whether centrosome aberrations contribute to cancer development or progression, and, if so, through what mechanisms. More recent studies have begun to explore the impact of centrosome aberrations on tissue architecture and, potentially, metastatic invasion [16,20,21,22,23]. Most of these studies made use of three-dimensional (3D) culture models based on acini derived
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