Defects in bipolar spindle assembly and spindle assembly checkpoint function explain CIN in only a small subset of aneuploid tumor cells, leaving the underlying causes of CIN in most aneuploid cells undetermined. This indicates that alternative mechanisms beyond these well-characterized mitotic defects must account for chromosome missegregation in the majority of CIN tumor cells. [@thompson_examining_2008]
Definitions
- chromosomal instability
- bipolar spindle assembly
- multipolar spindles
- spindle assembly checkpoint
- anaphase
- chromosome missegregation
- aneuploid
- tumor cells
Synthesis
Multiple lines of evidence establish that chromosomal instability in cells with supernumerary centrosomes arises independently of the classic mitotic defects historically assumed to drive chromosome segregation errors, such as multipolar divisions or spindle assembly checkpoint failure. The mechanistic relationship centers on merotelic kinetochore-microtubule attachments that accumulate during a transient multipolar spindle intermediate state before centrosomes cluster to enable bipolar division, with these merotelic errors persisting into anaphase and causing elevated lagging chromosome frequencies even when cells complete ostensibly normal bipolar divisions. This pathway demonstrates that extra centrosomes promote chromosome missegregation through a subtle attachment defect rather than through overt structural catastrophes like multipolar divisions, which are rare and typically produce inviable progeny insufficient to account for observed chromosomal instability rates. The key unresolved aspect is whether this merotely-driven chromosomal instability mechanism operates uniformly across different cellular contexts, particularly given that chromosome missegregation alone is insufficient for aneuploid cell propagation without additional phenotypic adaptations that remain incompletely characterized.
Related
- Stat1 inactivation mechanism is conserved between mouse and human aneuploid cancers
- Mps1 truncation-induced CIN generates convergent recurrent chromosome gains
- Multipolar spindle intermediate allows merotelic attachment accumulation
- Merotely causes chromosome missegregation in unstable cells
- Multipolar divisions are rare and typically produce inviable progeny
- Aneuploidy increases spontaneous tumor formation in aged animals
- Increased aneuploidy inhibits chemically and genetically induced tumorigenesis
- Aneuploid tumors inactivate Stat1 signaling with increased Myc activity
- Extra centrosomes correlate with chromosomal instability in tumors
- Stat1 loss combined with Myc activation alleviates CIN-induced immune infiltration
- Extra centrosomes promote chromosome missegregation during bipolar division
- Single-cell sequencing reveals karyotype heterogeneity in lymphomas
- Aneuploidy exhibits dual roles as oncogenic and tumor-suppressive
- CIN causality toward aneuploidy was previously unanswered
- Elevated merotely generates CIN in stable near-diploid cells
- CENP-E reduction generates aneuploidy and chromosomal instability
- Missegregation alone insufficient for aneuploid cell propagation