CIN and Aneuploidy: Different Concepts, Different Consequences

Abstract

Chromosomal instability (CIN) and aneuploidy are similar concepts but not synonymous. CIN is the process that leads to chromosome copy number alterations, and aneuploidy is the result. While CIN and resulting aneuploidy often cause growth defects, they are also selected for in cancer cells. Although such contradicting fates may seem paradoxical at first, they can be better understood when CIN and aneuploidy are assessed separately, taking into account the in vitro or in vivo context, the rate of CIN, and severity of the aneuploid karyotype. As CIN can only be measured in living cells, which proves to be technically challenging in vivo, aneuploidy is more frequently quantified. However, CIN rates might be more predictive for tumor outcome than assessing aneuploidy rates alone. In reviewing the literature, we therefore conclude that there is an urgent need for new models in which we can monitor chromosome mis-segregation and its consequences in vivo. Also see the video abstract here: https://youtu.be/fL3LxZduchg

Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition

“…We, therefore, reasoned that targeting RNA or protein processing, transcriptional regulation, apoptosis, or DNA repair might be particularly toxic to aneuploid cells and cells exhibiting a CIN phenotype. As CIN and aneuploidy are different concepts (Schukken & Foijer, 2018) and have different consequences for cells (Stingele et al, 2012;Andriani et al, 2016;Schukken & Foijer, 2018) aneuploidy and CIN might impose different therapeutic vulnerabilities. To test this, we performed two small-scale drug screens, one to identify compounds that selectively prevent the propagation of aneuploid cells and another to identify small molecules that selectively targets CIN cells.…”

“…Although CIN and aneuploidy are intimately related, CIN has additional effects on cell physiology and growth in addition to those imposed by the resulting aneuploidy (Schukken and Foijer, 2018). Because CIN drives karyotype heterogeneity, thus increasing the rate of evolution that cancer cells use to acquire new features and adapt (McGranahan et al, 2012;Giam & Rancati, 2015), targeting CIN would provide an even more powerful means to kill cancer cells than aneuploidy alone.…”

Multi-omic analysis of CIC’s functional networks reveals novel interaction partners and a potential role in mitotic fidelity

“…CS defects such as those observed in our CIC KO lines, including the presence of micronuclei and lagging chromosomes, have been linked to copy number alterations in daughter cells [30][31][32] . To determine whether evidence of copy number defects could be observed in CICdeficient cells, we performed single-cell genome sequencing (DLP+ 33 ) on DNA libraries from the parental CIC WT NHA line and NHA-derived CIC KO lines (A2 and H9 described above, and additional lines B6 and H10).…”

Altering microtubule dynamics is synergistically toxic with inhibition of the spindle checkpoint

“…We therefore reasoned that targeting RNA or protein processing, transcriptional regulation, apoptosis, or DNA repair might be particularly toxic to aneuploid cells and cells exhibiting a CIN phenotype. As CIN and aneuploidy are different concepts (Schukken & Foijer, 2017) and have different consequences for cells (Schukken & Foijer, 2017; Stingele et al , 2012; Andriani et al , 2016), aneuploidy and CIN might impose different therapeutic vulnerabilities. To test this, we performed two small-scale drug screens, one to identify compounds that selectively kill aneuploid cells and another to identify small molecules that selectively kill CIN cells.…”

“…While CIN and aneuploidy are intimately related, CIN has additional effects on cell physiology and growth in addition to those imposed by the resulting aneuploidy (Schukken & Foijer, 2017). Since CIN drives karyotype heterogeneity thus increasing the rate of evolution that cancer cells use to acquire new features and adapt (Giam & Rancati, 2015; McGranahan et al , 2012), targeting CIN would provide an even more powerful means to kill cancer cells than aneuploidy alone.…”