Structural centrosome aberrations sensitize polarized epithelia to basal cell extrusion

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.

CEP131 Abrogates CHK1 Inhibitor-Induced Replication Defects and Is Associated with Unfavorable Outcome in Neuroblastoma

“…Furthermore, overexpression in colon cancer HCT116 cells accelerated tumor formation and growth in nude mice [ 24 ], and this was consistent with the findings of a previous study showing that tumor growth was significantly suppressed in athymic mice transplanted breast cancer MCF-7 cells in which CEP131 expression was depleted [ 14 ]. Taken together, these observations indicate that the increased expression of CEP131 can result in disrupting proper centrosome duplication leading to aneuploidy and chromosomal instability [ 14 , 24 , 26 ]; activating proliferative pathway such as ERK and AKT signaling [ 15 , 16 ]; inducing primary cilium [ 22 , 27 ] and subsequent activation of Sonic Hedgehog pathway [ 23 ]; disrupting tissue architecture caused by centrosome aberrations leading to dissemination of potentially metastatic cells [ 28 ].…”

The Emerging Link between Centrosome Aberrations and Metastasis

“…Structural abnormalities such as altered centrosome size or shape and increased centriole length have also been observed in tumors (Marteil et al, 2018;Lingle and Salisbury, 1999;Lingle et al, 1998). Although structural and numerical alterations often co-occur in tumors and induce some common effects, they can also promote mechanistically distinct cell behaviors as described further below (Arnandis et al, 2018;Ganier et al, 2018a;Ganier et al, 2018b;.…”

“…Structural and numerical centrosome alterations can, therefore, reorganize the microtubule cytoskeleton and disrupt tissue architecture, potentially providing a platform for metastatic cell dissemination (Nigg et al, 2017;Schnerch and Nigg, 2016). Indeed, recent work shows that centrosome aberrations may facilitate the dissemination of potentially metastatic cells through multiple distinct mechanisms (Arnandis et al, 2018;Ganier et al, 2018a;Ganier et al, 2018b;. In this review, we first outline the key steps required for metastasis and then discuss work suggesting that centrosome aberrations can contribute to the initial steps in the metastatic cascade.…”

“…Similar to oncogenic mutations, centrosome structural aberrations induced by overexpression of Nlp have been shown to sensitize damaged epithelial cells to basal extrusion (Figure 1D). In addition, overexpression of the centrosome protein CEP131 creates distinct alterations in the centrosome structure that promote the basal extrusion of dying cells with CEP131-induced structural centrosome aberrations in the absence of any external damaging agent (Ganier et al, 2018a). If extruded cells harbor additional oncogenic alterations that promote survival, it is plausible that a reversal in the directionality of cell extrusion caused by centrosome aberrations could contribute to the dissemination of metastatic cells.…”

The Function of BARD1 in Centrosome Regulation in Cooperation with BRCA1/OLA1/RACK1

“…For example, centrosome amplification increases Rac1 activity, disrupting cell-cell adhesion and promoting cellular invasion [20]; it also promotes paracrine invasion by inducing the secretion of pro-invasive factors, including interleukin-8 [21]. Structural centrosome aberrations promote non-cell-autonomous dissemination of mitotic cells and extrusion of damaged cells from polarized epithelia, which are the initial steps of the metastatic process [22,23].…”