Oxidative Stress in Cells with Extra Centrosomes Drives Non-Cell-Autonomous Invasion

Teresa Arnandis,Pedro Monteiro,Sophie D Adams,Victoria Louise Bridgeman,Vinothini Rajeeve,Emanuela Gadaleta,Jacek Marzec,Claude Chelala,Ilaria Malanchi,Pedro R Cutillas,Susana A Godinho

doi:10.1016/j.devcel.2018.10.026

Teresa Arnandis, Pedro Monteiro + Show 9 more

Open Access

https://doi.org/10.1016/j.devcel.2018.10.026

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Abstract

SummaryCentrosomal abnormalities, in particular centrosome amplification, are recurrent features of human tumors. Enforced centrosome amplification in vivo plays a role in tumor initiation and progression. However, centrosome amplification occurs only in a subset of cancer cells, and thus, partly due to this heterogeneity, the contribution of centrosome amplification to tumors is unknown. Here, we show that supernumerary centrosomes induce a paracrine-signaling axis via the secretion of proteins, including interleukin-8 (IL-8), which leads to non-cell-autonomous invasion in 3D mammary organoids and zebrafish models. This extra centrosomes-associated secretory phenotype (ECASP) promotes invasion of human mammary cells via HER2 signaling activation. Further, we demonstrate that centrosome amplification induces an early oxidative stress response via increased NOX-generated reactive oxygen species (ROS), which in turn mediates secretion of pro-invasive factors. The discovery that cells with extra centrosomes can manipulate the surrounding cells highlights unexpected and far-reaching consequences of these abnormalities in cancer.

Highlights

The centrosome is the principal microtubule (MT) organizing center in animal cells and consists of a pair of centrioles surrounded by the pericentriolar material (PCM) (Bettencourt-Dias and Glover, 2007)
Centrosome Amplification Induces Paracrine Invasion To investigate whether the presence of extra centrosomes promotes non-cell-autonomous functions, we took advantage of non-transformed cells to avoid additional effects caused by cancer mutations
To do so, conditioned media (CM) was collected from our previously established human mammary epithelial cell line MCF10A.Polo-like kinase 4 (PLK4) where centrosome amplification is driven by transient induction of PLK4 upon doxycycline (DOX) treatment (Godinho et al, 2014) (Figure S1A)

Summary

Introduction

The centrosome is the principal microtubule (MT) organizing center in animal cells and consists of a pair of centrioles surrounded by the pericentriolar material (PCM) (Bettencourt-Dias and Glover, 2007). The importance of the centrosome cycle is emphasized by its tight regulation and conservation throughout evolution (Nigg and Stearns, 2011; Werner et al, 2017). Mounting evidence indicates that extra centrosomes are not bystanders of tumor progression and can directly impact tumorigenesis by generating aneuploidy and promoting the acquisition of invasive traits (Ganem et al, 2009; Godinho et al, 2014). Recently developed mouse models demonstrated that induction of centrosome amplification, via transient Polo-like kinase 4 (PLK4) overexpression, accelerates tumorigenesis in the absence of the tumor suppressor p53 (Coelho et al, 2015; Sercin et al, 2016) and promotes tumor formation in p53-proficient mice (Levine et al, 2017). Centrosome amplification can play a role in the initiation and progression of tumors

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