期刊
DEVELOPMENTAL CELL
卷 47, 期 4, 页码 409-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2018.10.026
关键词
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资金
- Cancer Research UK Centre [C16420/A18066]
- BBSRC [BB/M006174/1]
- Barts
- London Charity [297/2249]
- Medical Research Council [MR/M010414/1]
- BBSRC [BB/M006174/1] Funding Source: UKRI
- MRC [MR/M010414/1] Funding Source: UKRI
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.
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