APC-mutant cells exploit compensatory chromosome alterations to restore tumour cell fitness

Author:

Kawasaki Yoshihiro,Hamaji Tomoko,Owada Koji,Hayashi Akiko,Wu Yuping,Nogi Taisaku,Okada Miwa,Sakai Shoko,Tokushige Naoko,Kouyama Yuta,Niida Atsushi,Mimori Koshi,Kuroda Toshihiko,Senda Takao,Ohsugi MihoORCID,Fumoto Katsumi,Kikuchi Akira,Widlund Per O.,Kiyosue Kazuyuki,Yamashita Norio,Morita Masahiko,Yokota Hideo,Arjunan Satya N. V.,Chew Wei-Xiang,Takahashi Koichi,Legant Wesley R.,Chen Bi-Chang,Betzig Eric,Smits Ron,Fodde RiccardoORCID,Oshima Hiroko,Oshima Masanobu,Taketo M. Mark,Akiyama Tetsu,Mimori-Kiyosue Yuko

Abstract

AbstractCertain copy number alterations (CNAs) are strongly associated with particular cancer types. However, the mechanisms that underlie selection of specific CNAs remain unknown. Here, we identified functional relationships between recurrent CNAs in colorectal cancers (CRCs) and adenomatous polyposis coli (APC) mutations. Quantitative phenotyping of mitotic spindles highlighted APC functions at centrosomes where APC positively regulated Aurora A kinase (AURKA). Upon APC inactivation, elevated β-catenin levels blocked AURKA activation, which caused chromosome instability and suppressed proliferation, resulting in the generation and selection of AURKA-activating CNAs. Arm-level amplification of chromosomes that contained AURKA and AURKA activator genes was observed in APC-mutant CRCs, early stage mouse tumours, and cells in culture, which was concomitant with an increase in growth potential. Our findings demonstrate a mechanism that restores tumour cell fitness through compensatory chromosome alterations to overcome adverse effects of prior mutations, which may affect the course of cancer type-specific CNA formation.

Publisher

Cold Spring Harbor Laboratory

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