APC mutant cells exploit compensatory chromosome alterations to restore tumour cell fitness
Per O Widlund,
Satya N. V. Arjunan,
Wesley R Legant,
M. Mark Taketo,
Posted 18 Sep 2020
bioRxiv DOI: 10.1101/2020.09.18.303016
Posted 18 Sep 2020
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 β-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. ### Competing Interest Statement Portions of the technology described herein are covered by U.S. Patent 7,894,136 issued to Eric Betzig (EB) and assigned to Lattice Light, LLC of Ashburn, VA, U.S. Patents 8,711,211 and 9,477,074 issued to EB and assigned to HHMI, U.S. Patent application 13/844,405 filed by EB and Kai Wang (KW) and assigned to HHMI, and U.S. Patent 9,500,846 issued to EB and KW and assigned to HHMI.
- Downloaded 165 times
- Download rankings, all-time:
- Site-wide: 114,788
- In cell biology: 5,291
- Year to date:
- Site-wide: 57,260
- Since beginning of last month:
- Site-wide: 51,593
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!