Centrosome loss results in an unstable genome and malignant prostate tumors

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Abstract

Localized, nonindolent prostate cancer (PCa) is characterized by large-scale genomic rearrangements, aneuploidy, chromothripsis, and other forms of chromosomal instability (CIN), yet how this occurs remains unclear. A well-established mechanism of CIN is the overproduction of centrosomes, which promotes tumorigenesis in various mouse models. Therefore, we developed a single-cell assay for quantifying centrosomes in human prostate tissue. Surprisingly, centrosome loss—which has not been described in human cancer—was associated with PCa progression. By chemically or genetically inducing centrosome loss in nontumorigenic prostate epithelial cells, mitotic errors ensued, producing aneuploid, and multinucleated cells. Strikingly, transient or chronic centrosome loss transformed prostate epithelial cells, which produced highly proliferative and poorly differentiated malignant tumors in mice. Our findings suggest that centrosome loss could create a cellular crisis with oncogenic potential in prostate epithelial cells.

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Acknowledgements

We thank K. Oegema for providing centrinone and CRISPR constructs, D. Pellman for histone-H2B construct, V. Bautch for centrin1 construct, W. Hahn for PrEC cells, C. Miranti for iPEC37 cells, and N. Ellis and J. DeLuca for technical advice. Tissue samples were obtained from the PCa Biorepository Network (PCBN) (DoD PCa Research Program Award No W81XWH-14-2-0182, W81XWH-14-2-0183, W81XWH-14-2-0185, W81XWH-14-2-0186, and W81XWH-15-2-0062). This work was supported by NIH grants NCI P30 CA23074, R01GM110166, and R01GM126035 to GCR, R01CA159406 to AEC and Tim and Diane Bowden Cancer Biology Research Fellowship to MW.

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Correspondence to Anne E. Cress or Gregory C. Rogers.

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