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

Centrosomal 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. [Display omitted] •Centrosome amplification induces non-cell-autonomous invasion•Oxidative stress leads to the secretion of pro-invasive factors•IL-8 is a major ROS-mediated secreted factor important for paracrine invasion•High ROS can lead to a senescence-like phenotype in cells with extra centrosomes Arnandis et al. uncovered a non-cell-autonomous function for centrosome amplification in cancer. Cells with extra centrosomes induce paracrine invasion via secretion of pro-invasive factors. Altered secretion is partly regulated by elevated reactive oxygen species in cells with extra centrosomes. This work highlights far-reaching consequences of centrosome amplification in cancer.