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

Abstract

SUMMARY Aneuploidy, a state of karyotype imbalance, is a hallmark of cancer. Changes in chromosome copy number have been proposed to drive disease by modulating the dosage of cancer driver genes and by promoting cancer genome evolution. Given the potential of cells with abnormal karyotypes to become cancerous, do pathways exist that limit the prevalence of such cells? By investigating the immediate consequences of aneuploidy on cell physiology, we identified mechanisms that eliminate aneuploid cells. We find that chromosome mis-segregation leads to further genomic instability that ultimately causes cell cycle arrest. We further show that cells with complex karyotypes exhibit features of senescence and produce pro-inflammatory signals that promote their clearance by the immune system. We propose that cells with abnormal karyotypes generate a signal for their own elimination that may serve as a means for cancer cell immunosurveillance.

Cellular Stress Associated with Aneuploidy

“…This study revealed that aneuploid cells may replicate some of their DNA with different polymerases than euploid cells. Consistent with results in budding yeast, DNA damage markers such as 53BP1 foci accumulated in aneuploid human RPE-1 cells (Santaguida et al, 2017). The accumulation of break point junction patterns suggestive of replication defects was observed in specific trisomic and tetrasomic human cells (Passerini et al, 2016).…”

“…In fact, in many aneuploid yeast strains with simple or complex chromosome stoichiometry (Pavelka et al, 2010), a propensity for protein aggregation was not evident (our unpublished observations). Studies that involved acute induction of aneuploidy in mammalian cell lines may be complicated by the possible presence of genotoxic or metabolic stress in these cells, which are also known to induce autophagy (Balaburski et al, 2010; Santaguida et al, 2017; Santaguida et al, 2015; Soto et al, 2017; White, 2016; Xiao et al, 2015). Finally, the extent to which an aneuploid genome can tolerate extra protein expression may vary greatly from karyotype to karyotype.…”

“…Indeed, several recent studies highlight replication stress caused by aneuploidy. For example, induction of simple aneuploidy in RPE-1 cells with an MPS1 inhibitor, which was defined by cells with genome imbalances that contained less than 5% of their genome, was shown to lead to a significant reduction in fork rate and increased replication fork stalling when compared to untreated euploid cells (Santaguida et al, 2017). Slower replication rates were also observed in trisomic and tetrasomic cells derived from both RPE-1 and HCT116 cell lines (Passerini et al, 2016).…”

CIN and Aneuploidy: Different Concepts, Different Consequences

“…[5,17,18,23,70] These mis-segregation events will lead to karyotype heterogeneity and karyotype evolution in the cell population and might explain the low rate of aneuploidy and karyotype evolution in cell cultures in which no (additional) CIN is induced (see Figure 2a for an example of karyotype evolution with low CIN). However, whether this "low-grade background" CIN rate is representative for the in vivo situation still needs to be assessed.…”

“…Strikingly, the aneuploidy-induced senescent cells were selectively eliminated compared to the euploid control cells, suggesting that aneuploid www.advancedsciencenews.com www.bioessays-journal.com cells can trigger an immune response. [70] Furthermore, the innate immune system was recently found to detect DNA in micronuclei through cytosolic nucleic acid sensor (cGAS)-mediated surveillance, [77] which could be another way our immune system detects aneuploid cells. While these observations collectively indicate that CIN might be tolerated by some tissues when provoked later during development, further work is required to investigate the fate of CIN cells over time and their possible clearance by the immune system in vivo.…”