Centrosome Amplification Is Sufficient to Promote Spontaneous Tumorigenesis in Mammals

• Published in: Developmental cell Vol. 40; no. 3; pp. 313 - 322.e5
• Main Authors: Levine, Michelle S., Bakker, Bjorn, Boeckx, Bram, Moyett, Julia, Lu, James, Vitre, Benjamin, Spierings, Diana C., Lansdorp, Peter M., Cleveland, Don W., Lambrechts, Diether, Foijer, Floris, Holland, Andrew J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.02.2017; Elsevier
• Subjects: Aneuploidy; Animals; Carcinogenesis - metabolism; Carcinogenesis - pathology; centriole; Centrosome - metabolism; centrosome amplification; Epidermis - metabolism; genomic instability; Intestinal Neoplasms - pathology; Life Sciences; Mammals - metabolism; Mice, Inbred C57BL; mitosis; Organ Specificity; Plk4; Protein Serine-Threonine Kinases - metabolism; tumorigenesis; centrosome amplification; Plk4; aneuploidy; tumorigenesis; centriole; mitosis; genomic instability
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2016.12.022

Centrosome amplification is a common feature of human tumors, but whether this is a cause or a consequence of cancer remains unclear. Here, we test the consequence of centrosome amplification by creating mice in which centrosome number can be chronically increased in the absence of additional genetic defects. We show that increasing centrosome number elevated tumor initiation in a mouse model of intestinal neoplasia. Most importantly, we demonstrate that supernumerary centrosomes are sufficient to drive aneuploidy and the development of spontaneous tumors in multiple tissues. Tumors arising from centrosome amplification exhibit frequent mitotic errors and possess complex karyotypes, recapitulating a common feature of human cancer. Together, our data support a direct causal relationship among centrosome amplification, genomic instability, and tumor development. [Display omitted] •Plk4 overexpression promotes persistent centrosome amplification in vivo•Centrosome amplification promotes aneuploidy in vivo•Extra centrosomes promote tumor initiation in a model of intestinal neoplasia•Centrosome amplification drives spontaneous tumorigenesis Extra centrosomes are common in human cancers and are correlated with aneuploidy and poor patient prognosis. However, whether supernumerary centrosomes are a cause or consequence of tumorigenesis is still unclear. Levine et al. now demonstrate that centrosome amplification is sufficient to drive tumorigenesis in multiple tissues of mice.