Unlocking the intrinsic effect of CIN in intestinal organoids

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.