Aneuploid tumors specifically inactivate Stat1 signaling while simultaneously increasing Myc activity to adapt to the stress induced by chromosomal instability. This combined genetic alteration is enriched in chromosomally unstable tumors and represents a mechanism by which aneuploid cells achieve malignant transformation in vivo. [@schubert_cancer_2021]
Definitions
- aneuploidaneuploidy
- chromosomal instability
- tumor
- chromosomally unstable tumors
- stat1 signaling
- Aneuploid
- tumors
- Myc activity
- aneuploid cells
- in vivo
Synthesis
Multiple lines of evidence establish that aneuploid tumors with chromosomal instability specifically inactivate Stat1 signaling while concurrently increasing Myc activity as a conserved mechanism to evade immune surveillance. This dual genetic alteration directly counteracts the fitness cost that chromosomal instability normally imposes: chromosomally unstable tumors experience increased immune cell infiltration, but the combination of Stat1 loss and Myc activation suppresses this immune response and allows aneuploid cells to persist despite aneuploidy-induced stress. The mechanism is conserved between mouse and human aneuploid cancers, indicating an evolutionary solution distinct from the more common but non-enriched p53 loss pathway. While the immune evasion function of this dual alteration is well-supported, what remains contested is the broader question of whether aneuploidy acts primarily as tumor-promoting or tumor-suppressive, since increased aneuploidy both drives spontaneous tumor formation in aged animals yet inhibits chemically and genetically induced tumorigenesis in other contexts.
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
- Subclonal driver events determine therapy response and tumor evolution
- Hypoxia-related transcriptional programs are variably expressed in glioblastoma cells
- Multipolar divisions are rare and typically produce inviable progeny
- Aneuploid cancers inactivate Stat1 to circumvent immune surveillance
- Different aneuploid cells share common fitness-related traits
- Aneuploidy increases spontaneous tumor formation in aged animals
- Increased aneuploidy inhibits chemically and genetically induced tumorigenesis
- Extra centrosomes correlate with chromosomal instability in tumors
- 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
- Glioblastoma cells exhibit continuum of stemness-related expression states
- 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
- Tumors contain multiple subclones with spatial and temporal heterogeneity