Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells.

Alexander D Rhys,Andrew Mcainsh,Erik Sahai,Guillaume Charras,Teresa Arnandis,Christopher Smith,Susana A Godinho,Malti Vaghela,Pedro Monteiro,Takuya Kato,Birgit Leitinger

doi:10.1083/jcb.201704102

Abstract

Centrosome amplification is a common feature of human tumors. To survive, cancer cells cluster extra centrosomes during mitosis, avoiding the detrimental effects of multipolar divisions. However, it is unclear whether clustering requires adaptation or is inherent to all cells. Here, we show that cells have varied abilities to cluster extra centrosomes. Epithelial cells are innately inefficient at clustering even in the presence of HSET/KIFC1, which is essential but not sufficient to promote clustering. The presence of E-cadherin decreases cortical contractility during mitosis through a signaling cascade leading to multipolar divisions, and its knockout promotes clustering and survival of cells with multiple centrosomes. Cortical contractility restricts centrosome movement at a minimal distance required for HSET/KIFC1 to exert its function, highlighting a biphasic model for centrosome clustering. In breast cancer cell lines, increased levels of centrosome amplification are accompanied by efficient clustering and loss of E-cadherin, indicating that this is an important adaptation mechanism to centrosome amplification in cancer.

Highlights

The presence of supernumerary centrosomes is a hallmark of human tumors (Zyss and Gergely, 2009; Chan, 2011)
It is thought that cells are unlikely to require adaptation to centrosome amplification, which is further supported by the fact that most cancer cell lines with extra centrosomes are able to cluster centrosomes efficiently (Ring et al, 1982; Quintyne et al, 2005; Kwon et al, 2008; Ganem et al, 2009)
We demonstrate that induction of centrosome amplification in a panel of nontransformed cell lines reveals intrinsic differences in clustering ability, with epithelial cells displaying an inefficient process

Summary

Introduction

The presence of supernumerary centrosomes is a hallmark of human tumors (Zyss and Gergely, 2009; Chan, 2011). Recent work has shown that these abnormalities can accelerate and promote tumorigenesis in vivo, induce aneuploidy, and promote cell invasion (Ganem et al, 2009; Silkworth et al, 2009; Godinho et al, 2014; Coelho et al, 2015; Serçin et al, 2016; Levine et al, 2017). Most cancer cell lines with high levels of centrosome amplification (as defined by >30% of cells containing extra centrosomes) are highly proficient at clustering extra centrosomes (Ring et al, 1982; Quintyne et al, 2005; Kwon et al, 2008; Ganem et al, 2009).

Methods

Results

Conclusion