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

Dev Cell. 2018 Nov 19;47(4):409-424.e9. doi: 10.1016/j.devcel.2018.10.026.


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.

Keywords: HER2; IL-8; ROS; cancer; centrosome amplification; invasion; paracrine signaling; secretion; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast / metabolism
  • Breast / pathology
  • Cell Transformation, Neoplastic / pathology*
  • Centrosome / metabolism
  • Centrosome / pathology*
  • Humans
  • Mitosis / physiology*
  • Neoplasms / pathology
  • Oxidative Stress / physiology*
  • Signal Transduction / physiology