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APC/C dysfunction limits excessive cancer chromosomal instability
Sansregret L1; Patterson JO1; Dewhurst S1; López-García C1; Koch A2; McGranahan N1,3; Chao WCH1; Barry DJ1; Rowan A1; Instrell R1; Horswell S1; Way M1; Howell M1; Singleton MR1; Medema RH2; Nurse P1; Petronczki M1,4; Swanton C1,3
Source PublicationCancer Discovery

Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization. APC/C impairment caused adaptation to MPS1 inhibitors, revealing a likely resistance mechanism to therapies targeting the spindle assembly checkpoint. Finally, CRISPR-mediated introduction of cancer somatic mutations in the APC/C subunit cancer driver gene CDC27 reduces chromosome segregation errors, whereas reversal of an APC/C subunit nonsense mutation increases CIN. Subtle variations in mitotic duration, determined by APC/C activity, influence the extent of CIN, allowing cancer cells to dynamically optimize fitness during tumor evolution.

Indexed BySCIE
WOS Research AreaOncology
WOS SubjectOncology
WOS IDWOS:000396018000027
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Cited Times [WOS]:49   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorPetronczki M; Swanton C
Affiliation1.The Francis Crick Institute, London, United Kingdom
2.The Francis Crick Institute, London, United Kingdom
3.CRUK UCL/Manchester Lung Cancer Centre of Excellenc
4.Boehringer Ingelheim, Vienna, Austria
Corresponding Author AffilicationCancer Centre
Recommended Citation
GB/T 7714
Sansregret L,Patterson JO,Dewhurst S,et al. APC/C dysfunction limits excessive cancer chromosomal instability[J]. Cancer Discovery,2017,7(2).
APA Sansregret L.,Patterson JO.,Dewhurst S.,López-García C.,Koch A.,...&Swanton C.(2017).APC/C dysfunction limits excessive cancer chromosomal instability.Cancer Discovery,7(2).
MLA Sansregret L,et al."APC/C dysfunction limits excessive cancer chromosomal instability".Cancer Discovery 7.2(2017).
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