APC-mutant cells exploit compensatory chromosome alterations to restore tumour cell fitness
By
Yoshihiro Kawasaki,
Tomoko Hamaji,
Koji Owada,
Akiko Hayashi,
Yuping Wu,
Taisaku Nogi,
Miwa Okada,
Shoko Sakai,
Naoko Tokushige,
Yuta Kouyama,
Atsushi Niida,
Koshi Mimori,
Toshihiko Kuroda,
Takao Senda,
Miho Ohsugi,
Katsumi Fumoto,
Akira Kikuchi,
Per O Widlund,
Kazuyuki Kiyosue,
Norio Yamashita,
Masahiko Morita,
Hideo Yokota,
Satya N. V. Arjunan,
Wei-Xiang Chew,
Koichi Takahashi,
Wesley R Legant,
Bi-Chang Chen,
Eric Betzig,
Ron Smits,
Riccardo Fodde,
Hiroko Oshima,
Masanobu Oshima,
M. Mark Taketo,
Tetsu Akiyama,
Yuko Mimori-Kiyosue
Posted 18 Sep 2020
bioRxiv DOI: 10.1101/2020.09.18.303016
Certain copy number alterations (CNAs) are strongly associated with particular cancer types. However, the mechanisms underlying the 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 {beta}-catenin levels blocked AURKA activation, which caused chromosome instability and supressed proliferation, resulting in the generation and selection of AURKA-activating CNAs. Arm-level amplification of chromosomes containing 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.
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