Chromosome instability is a hallmark of many tumors and correlates with the presence of extra centrosomes. However, a direct mechanistic link between extra centrosomes and CIN had not been previously established. [@ganem_mechanism_2009]
Definitions
Synthesis
It is well-established across multiple sources that extra centrosomes are associated with chromosomal instability in tumors, though the mechanistic relationship is more complex than initially presumed. While extra centrosomes can promote chromosome missegregation during cell division, multipolar divisions themselves are rare and typically produce inviable progeny, indicating that the presence of supernumerary centrosomes must drive chromosomal instability through alternative mechanisms, such as transient multipolar spindle intermediates that allow merotelic kinetochore attachments to accumulate before bipolar division. The relationship between chromosomal instability and tumor progression remains contested, as aneuploidy exhibits dual roles depending on context: elevated chromosomal instability drives spontaneous tumor formation in aged animals but paradoxically inhibits chemically or genetically induced tumorigenesis, suggesting that the fitness consequences of chromosomal instability vary with the initiating oncogenic event. Furthermore, chromosomally unstable tumors must overcome immune surveillance triggered by their aneuploid state, with evidence showing that aneuploid cancers consistently inactivate Stat1 signaling while increasing Myc activity to evade immune-mediated elimination, representing a conserved evolutionary solution that enables chromosomally unstable cells to achieve malignancy.
Related
- Stat1 inactivation mechanism is conserved between mouse and human aneuploid cancers
- Mps1 truncation-induced CIN generates convergent recurrent chromosome gains
- Chromosomal instability promotes immune cell infiltration into tumors
- Multipolar divisions are rare and typically produce inviable progeny
- Aneuploid cancers inactivate Stat1 to circumvent immune surveillance
- 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
- Stat1 loss combined with Myc activation alleviates CIN-induced immune infiltration
- CIN exists independently of classic mitotic defects in most cells
- Single-cell sequencing reveals karyotype heterogeneity in lymphomas
- Aneuploidy exhibits dual roles as oncogenic and tumor-suppressive
- CIN causality toward aneuploidy was previously unanswered
- p53 loss is common but not enriched in chromosomally unstable tumors
- CENP-E reduction generates aneuploidy and chromosomal instability
- Missegregation alone insufficient for aneuploid cell propagation