Structural centrosome aberrations promote non‐cell‐autonomous invasiveness

Abstract

Centrosomes are the main microtubule‐organizing centers of animal cells. Although centrosome aberrations are common in tumors, their consequences remain subject to debate. Here, we studied the impact of structural centrosome aberrations, induced by deregulated expression of ninein‐like protein (NLP), on epithelial spheres grown in Matrigel matrices. We demonstrate that NLP‐induced structural centrosome aberrations trigger the escape (“budding”) of living cells from epithelia. Remarkably, all cells disseminating into the matrix were undergoing mitosis. This invasive behavior reflects a novel mechanism that depends on the acquisition of two distinct properties. First, NLP‐induced centrosome aberrations trigger a re‐organization of the cytoskeleton, which stabilizes microtubules and weakens E‐cadherin junctions during mitosis. Second, atomic force microscopy reveals that cells harboring these centrosome aberrations display increased stiffness. As a consequence, mitotic cells are pushed out of mosaic epithelia, particularly if they lack centrosome aberrations. We conclude that centrosome aberrations can trigger cell dissemination through a novel, non‐cell‐autonomous mechanism, raising the prospect that centrosome aberrations contribute to the dissemination of metastatic cells harboring normal centrosomes.

Inhibition of CPAP –tubulin interaction prevents proliferation of centrosome‐amplified cancer cells

“…Centrosome amplification triggers cellular invasion in 3D cultures (Godinho et al , ; Ganier et al , ). To test whether CCB02‐mediated effects could impair the invasive behavior of NSCLC cells, we used 3D‐organotypic cultures of H1975 T790M and HCC827‐GR exhibiting resistance to EGFR‐TKIs.…”

“…In contrast, many cancer cells harbor extra centrosomes accompanied by chromosomal instability (Nigg, ). Thus, centrosome amplification and its structural aberrations is a hallmark of human cancers and has direct consequences on chromosomal instability and cancer cell invasion (Ganem et al , ; Godinho et al , ; Ganier et al , ; Marteil et al , ).…”

Pushed out of a tough crowd: centrosome aberrations promote invasiveness

“…To investigate the impact of centrosome aberrations in an intact epithelium, Ganier et al () employed overexpression of Ninein‐like protein (NLP) to model structural centrosome aberrations in 3D epithelial cultures. NLP is a centrosome protein that interacts with the γ‐tubulin ring complex to promote microtubule nucleation (Casenghi et al , ).…”

“…However, additional mechanisms for how centrosome aberrations impact tumor behavior have also been put forth, including recent work that showed centrosome amplification promotes invasive phenotypes in a 3D culture system by increasing Rac1 activity and disrupting cell–cell adhesion junctions (Godinho et al , ). The study by Ganier et al () now expands our understanding of the impact of centrosome aberrations in tumors by offering additional insight into a pathway through which centrosome aberrations can induce an invasive phenotype. Perhaps most importantly, the budding phenotype the authors observe is non‐cell‐autonomous, offering an explanation for how centrosome abnormities could contribute to metastasis, by disseminating cells that themselves do not harbor potentially deleterious centrosome alterations.…”

Low centrosome numbers correlate with higher aggressivity in ovarian cancer

“…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] . Importantly however, even if many studies have described numerical centrosome defects in cultured cancer cells only a limited number of studies tumors has analyzed centrosome number alterations in situ.…”