Structural centrosome aberrations promote non‐cell‐autonomous invasiveness

• Published in: The EMBO journal Vol. 37; no. 9
• Main Authors: Ganier, Olivier, Schnerch, Dominik, Oertle, Philipp, Lim, Roderick YH, Plodinec, Marija, Nigg, Erich A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.05.2018; Springer Nature B.V; John Wiley and Sons Inc
• Subjects: Aberration; Animals; Atomic force microscopy; biomechanical properties; Cell Line, Tumor; Centrosome - metabolism; Centrosome - pathology; Centrosomes; Cytoskeleton; Deregulation; Dogs; E-cadherin; EMBO03; EMBO05; EMBO06; Epithelium; Epithelium - metabolism; Epithelium - pathology; Heterogeneity; Humans; Invasiveness; Madin Darby Canine Kidney Cells; Metastases; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Microtubules; Mitosis; multicellular cooperation; Neoplasm Metastasis; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; non‐cell‐autonomous process; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Stiffness; structural centrosome aberrations; Tumors; Yeast; non‐cell‐autonomous process; invasiveness; biomechanical properties; multicellular cooperation; structural centrosome aberrations
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.201798576

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. Synopsis While tumorigenic effects of centrosome amplification are well‐understood, induction of structural centrosome aberrations by overexpression of ninein‐like protein (NLP) reveals an unexpected non‐cell‐autonomous mechanism for dissemination of mitotic cells from epithelia. NLP‐induced structural centrosome aberrations trigger budding of mitotic cells from polarized epithelia. Budding of mitotic cells is a non‐cell‐autonomous process. Budding mitotic cells need not themselves harbor centrosome aberrations. Excess NLP stabilizes centrosomal microtubules, weakens E‐Cadherin junctions, and increases cellular stiffness. Budding depends on disorganization of E‐Cadherin junctions and stiffness heterogeneity within the epithelium. Graphical Abstract Decreased adherence and increased stiffness of cells overexpressing centrosomal ninein‐like protein causes dissemination of wild‐type cells undergoing mitosis from mosaic epithelia.