APC/C dysfunction limits excessive cancer chromosomal instability
More about Open Access at the CrickAuthors list
Laurent Sansregret James O Patterson Sally Dewhurst Carlos López-García André Koch Nicholas McGranahan William Chong Hang Chao David Barry Andrew Rowan Rachael Instrell Stuart Horswell Michael Way Michael Howell Martin R Singleton René H Medema Paul Nurse Mark Petronczki Charles SwantonAbstract
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.
Journal details
Journal Cancer Discovery
Volume 7
Issue number 2
Pages 218-233
Available online
Publication date
Full text links
Publisher website (DOI) 10.1158/2159-8290.cd-16-0645
Figshare View on figshare
Europe PubMed Central 28069571
Pubmed 28069571
Keywords
Related topics
- Tumour Biology
- Synthetic Biology
- Structural Biology & Biophysics
- Signalling & Oncogenes
- Model Organisms
- Infectious Disease
- Imaging
- Human Biology & Physiology
- Genome Integrity & Repair
- Genetics & Genomics
- Computational & Systems Biology
- Chemical Biology & High Throughput
- Cell Cycle & Chromosomes
- Cell Biology
- Biochemistry & Proteomics
Type of publication