10779/crick.12498035.v1 Teresa Arnandis Teresa Arnandis Pedro Monteiro Pedro Monteiro Sophie D Adams Sophie D Adams Victoria Louise Bridgeman Victoria Louise Bridgeman Vinothini Rajeeve Vinothini Rajeeve Emanuela Gadaleta Emanuela Gadaleta Jacek Marzec Jacek Marzec Claude Chelala Claude Chelala Ilaria Malanchi Ilaria Malanchi Pedro R Cutillas Pedro R Cutillas Susana A Godinho Susana A Godinho Oxidative stress in cells with extra centrosomes drives non-cell-autonomous invasion The Francis Crick Institute 2020 HER2 IL-8 ROS cancer centrosome amplification invasion paracrine signaling secretion senescence Breast Cell Transformation, Neoplastic Centrosome Humans Mitosis Neoplasms Oxidative Stress Signal Transduction Malanchi FC001112 06 Biological Sciences 11 Medical and Health Sciences Developmental Biology 2020-06-25 15:18:08 Journal contribution https://crick.figshare.com/articles/journal_contribution/Oxidative_stress_in_cells_with_extra_centrosomes_drives_non-cell-autonomous_invasion/12498035 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.