Centrosome amplification arises before neoplasia and increases upon p53 loss in tumorigenesis

Centrosome abnormalities are a typical hallmark of human cancers. However, the origin and dynamics of such abnormalities in human cancer are not known. In this study, we examined centrosomes in Barrett's esophagus tumorigenesis, a well-characterized multistep pathway of progression, from the premalignant condition to the metastatic disease. This human cancer model allows the study of sequential steps of progression within the same patient and has representative cell lines from all stages of disease. Remarkably, centrosome amplification was detected as early as the premalignant condition and was significantly expanded in dysplasia. It was then present throughout malignant transformation both in adenocarcinoma and metastasis. The early expansion of centrosome amplification correlated with and was dependent on loss of function of the tumor suppressor p53 both through loss of wild-type expression and hotspot mutations. Our work shows that centrosome amplification in human tumorigenesis can occur before transformation, being repressed by p53. These findings suggest centrosome amplification in humans can contribute to tumor initiation and progression.

Description

The uploaded article version is the Epub Ahead of Print version of the article, posted online 8 May 2018. It has been submitted to peer-review.
The deposited article version contains attached the supplementary materials within the pdf.

Keywords

Cancer human cancer Organelles Centrosome amplification p53

URI

http://hdl.handle.net/10400.7/867

Citation

Carla A.M. Lopes, Marta Mesquita, Ana Isabel Cunha, Joana Cardoso, Sara Carapeta, Cátia Laranjeira, António E. Pinto, José B. Pereira-Leal, António Dias-Pereira, Mónica Bettencourt-Dias, Paula Chaves (2018). Centrosome amplification arises before neoplasia and increases upon p53 loss in tumorigenesis.J Cell Biol May 2018, jcb.201711191; DOI: 10.1083/jcb.201711191