| dc.description.abstract | Most incidences of colorectal cancer (CRC) arise through Chromosomal Instability (CIN),
an ongoing process that imbalances the chromosome number. CIN manifests a dual role
in cancer, acting as both a tumor promoter and a tumor suppressor in a highly contextspecific manner. Its responses vary according to the tissue type and the degree to which
it occurs. This phenomenon is evident in CIN-driven tumorigenesis in the intestinal
region under an APCmin/+ background; in the small intestinal regions, tumour formation
occurred only after Moderate induction of CIN, while High CIN exerted a tumour
suppressive effect. In contrast, in the colonic region, both Moderate and High CIN
significantly triggered tumorigenesis. Interestingly, when tumours arise, they are
preferentially located in the distal parts of the small intestine and the colon. This study
aims to uncover the earliest effect of CIN in intestinal organoids in order to understand
why the same level of CIN leads to opposite outcomes between the two intestinal regions.
Using intestinal organoids for diverse degrees of CIN, our data suggest that in a tumorprone background, ileal organoids showed a gradual decrease in viability mirroring CIN
levels. In contrast, distal colonic organoids showed a higher tolerance for Moderate and
High CIN. This observation may partially explain the localized tumour burden upon
varying levels of CIN. However, we revealed that CIN-induced intestinal organoids had
low expansion potential. Since their survival in vivo leads to a higher tumor burden, we
reasoned that extrinsic factors, present in vivo, but absent in vitro, might be crucial for
their growth. Overall, this study shed light on how to use organoid systems to study the
impact of CIN. Future studies will be directed at understanding how CIN contributes to
cancer initiation and progression. | |
