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

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.

Patterns of selection against centrosome amplification in human cell lines

“…To this day, the contribution of centrosomal anomalies to cancer development remain controversial, with some studies showing that higher numbers, via Plk4 overexpression, can initiate or aggravate tumorigenesis (28,29), and others showing that it is not sufficient and may even slow down progression (30,31). On the other hand, extra centrioles are associated with other cancer hallmarks, such as aneuploidy (14,32) and invasion (33)(34)(35), and often correlate with a more aggressive cancer phenotype (3,7). The widespread occurrence of centriole number abnormalities in a cancer setting makes them an attractive as prospective biomarkers and as therapeutic targets (36).…”

Low centrosome numbers correlate with higher aggressivity in ovarian cancer

“…The findings that ovarian cancer cell lines containing extra centrosomes showed decreased mesothelial cell clearance capacity was surprising in light of the results found in breast cells 13,14 , suggesting once more that tissue specific properties influence the consequences of altered centrosome numbers. Ovarian tumors do not show typical invasion features seen in other tumor types 63 .…”

“…It has been shown that centrosome amplification induces invasive oncogenic-like features in a 3-D culture mammary cell (MCF10A) model, both in cell or non-cell autonomous manner 13,14 . Importantly, the levels of an activated form of RAC1, a small GTPase with described oncogenic signalling properties 13 , were increased.…”

“…When induced in breast epithelial cells, centrosome amplification resulted in the assembly of invasion-like features, which were RAC1dependent 13 . More recently, it has been shown that centrosome amplification can drive invasion in a non-cell autonomous manner through increased oxidative stress 14 . Non-cell autonomous detachment of mitotic tumor cells has also been described in organoids containing increased levels of Ninein-like protein, which induces centrosome structural defects [15][16][17] .…”

A pseudo-meiotic centrosomal function of TEX12 in cancer

“…Furthermore, it has been recently reported that supernumerary centrosomes induce the IL-8 paracrine-signalling axis in breast cancer, leading to increased migration and invasion of cells with amplified centrosomes into the wider cellular population. This could be especially important in tumours with TEX12 amplification, such as aggressive ovarian tumours (Fig 1a), as chromosomal TEX12 is proximal to IL-8 and hence both genes could easily be amplified together 39 . We propose that TEX12 constitutes a specific prognostic marker and a target for novel therapeutics and diagnostics in a number of human cancers.…”