Degree and site of chromosomal instability define its oncogenic potential

Abstract

Most human cancers are aneuploid, due to a chromosomal instability (CIN) phenotype. Despite being hallmarks of cancer, however, the roles of CIN and aneuploidy in tumor formation have not unequivocally emerged from animal studies and are thus still unclear. Using a conditional mouse model for diverse degrees of CIN, we find that a particular range is sufficient to drive very early onset spontaneous adenoma formation in the intestine. In mice predisposed to intestinal cancer (Apc Min/+ ), moderate CIN causes a remarkable increase in adenoma burden in the entire intestinal tract and especially in the distal colon, which resembles human disease. Strikingly, a higher level of CIN promotes adenoma formation in the distal colon even more than moderate CIN does, but has no effect in the small intestine. Our results thus show that CIN can be potently oncogenic, but that certain levels of CIN can have contrasting effects in distinct tissues.

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

“…Therefore, the propagation of CIN in cancer can arise through inactivation or bypass of the p53 pathway and the acquisition of mechanisms that allow tolerance of replication stress and aneuploidy-associated stressors, such as activation of the proteasome and autophagy and CIN adaptation [198,229,231]. While low and moderate levels of CIN may allow the evolution of advantageous karyotypes and the emergence of genomic alterations that provide resistance to therapy, tumors may not tolerate high CIN levels [232][233][234][235][236][237][238]. Interestingly, it has been reported that, in addition to acquiring CIN tolerance, tumors undergo CIN attenuation or buffering.…”

Acute systemic loss of Mad2 leads to intestinal atrophy in adult mice

“…Several mouse models have been engineered to study the effect of CIN on cancer initiation and progression 1 – 3 . These models have unequivocally shown that systemic high-grade CIN is incompatible with embryonic development and further that low-grade CIN predisposes to cancer, most efficiently when combined with other cancer predispositions such as p53 loss or APC mutation 1 – 3 , 22 . To circumvent CIN-induced embryonic lethality 5 , 23 , conditional mouse models were engineered in which CIN can be provoked in a tissue-specific fashion to study the consequences of chromosome mis-segregation in individual tissues in vivo 1 , 5 .…”

“…For instance, inducing CIN by inactivating Mad2 is incompatible with embryonic development 1 , often lethal to cultured cells 24 , and toxic to hair follicle stem cells 25 , but tolerated by basal epidermal cells 25 , T-cells 26 , and hepatocytes in vivo 26 . Furthermore, systemic CIN provoked in adult mice drives tumorigenesis in a dose-dependent fashion with medium CIN rates being most efficient 22 . Here, we study the effects of acute high-grade CIN in adult mice provoked by complete SAC alleviation and find that this leads to rapid regression of intestinal epithelia followed by significant weight loss and ultimately death.…”

Understanding How Genetic Mutations Collaborate with Genomic Instability in Cancer

“…Given that ongoing CIN is incompatible with early embryonic development [120], the most suitable CIN predisposition would be a conditional CIN-driving allele that does not efficiently promote cancer by itself. This could for instance be a Mps1 truncation or mutation allele [33,122], a Mad2 deletion allele [32], a hypomorphic BubR1 allele [123], or a Plk4 overexpression allele [24], as well as any other tissue-specific CIN driver. Indeed, in most of the CIN models, the CIN-driving allele alone leads to aneuploidy but not to rapid tumorigenesis.…”

“…Indeed, in most of the CIN models, the CIN-driving allele alone leads to aneuploidy but not to rapid tumorigenesis. However, combining CIN with a single mutation in p53 not only leads to cancer initiation [32,33,35,[122][123][124] but also to a significant reduction of tumor latency, which makes this setup very suitable for a mutagenesis screen.…”