APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability

Abstract

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. Significance We report a mechanism whereby cancers balance the evolutionary advantages associated with CIN against the fitness costs caused by excessive genome instability, providing insight into the consequence of CDC27 APC/C subunit driver mutations in cancer. Lengthening of mitosis through APC/C modulation may be a common mechanism of resistance to cancer therapeutics that increase chromosome segregation errors.

Cezanne/ OTUD 7B is a cell cycle‐regulated deubiquitinase that antagonizes the degradation of APC /C substrates

“…A likely cause of micronuclei formation is improper chromosome segregation. Notably, prior reports showed that restraining APC/C activity slows mitotic progression and reduces errors (Zeng et al , ; Sansregret et al , ). We analyzed lagging chromosomes, which cause aneuploidy and micronuclei, after depletion of Cezanne.…”

Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System

“…Aneuploid mammalian and yeast cells exhibit metabolic alterations (Williams et al, 2008), proliferation defects (Santaguida et al, 2015; Stingele et al, 2012; Tang et al, 2011; Thompson and Compton, 2010; Torres et al, 2007; Williams et al, 2008), genome instability (Blank et al, 2015; Meena et al, 2015; Ohashi et al, 2015; Passerini et al, 2016; Sheltzer et al, 2011; Zhu et al, 2012), proteotoxic stress (Oromendia et al, 2012; Santaguida et al, 2015; Santaguida and Amon, 2015b; Stingele et al, 2012; Tang and Amon, 2013), and aneuploid mammalian cells have been reported to activate p53 (Hinchcliffe et al, 2016; Li et al, 2010; López-García et al, 2017; Sansregret et al, 2017; Thompson and Compton, 2010). In addition to traits observed in a broad range of aneuploidies, aneuploid cells exhibit gene-specific phenotypes where changes in dosage of a particular gene cause a specific phenotype (i.e.…”

Tuning Chromosomal Instability to Optimize Tumor Fitness

“…In this issue, Sansregret et al (5) screen for cellular mechanisms to survive CIN due to partial inhibition of Mps1 (also known as TTK), a kinase necessary to sustain the mitotic checkpoint signal. The rate of CIN is directly proportional to the dose of Mps1 inhibitor.…”