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Colon cancer transformation revealed

Researchers from Max Planck and their collaborators have revealed the transformation of colon organoids in vitro.

Colorectal cancer

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. There is a range of evidence exploring the genetic landscape of mutations that drive carcinogenesis, including within the Wnt, KRAS, TGF-β, and p53 pathways. Constitutive activation of Wnt signalling, in particular, is considered to be a crucial feature of almost all CRCs. Experimental and patient data indicates that this event occurs early on in the CRC cascade. It is often achieved by mutation of APC and subsequent loss of heterozygosity. However, cases of CRC that are driven by chronic inflammatory disorders are associated with a distinct mutational profile. In these cases, mutations in the p53 pathways are thought to occur as an early event.

Recent data suggests that environmental factors are key drivers in CRC and that the colonic microbiota plays an important role in the development and progression of CRC. As well as inducing inflammation, certain microbes that colonise in the gut appear to also directly affect the genomic integrity of epithelial cells through genotoxins. For example, colibactin is a key genotoxin produced by several Enterobacteriaceae members, such as Escherichia coli. This toxin is encoded by the pks pathogenicity island. Several studies have shown that genotoxic colibactin-producing pks+ E. coli induce DNA double-strand breaks, mutations, and promote tumour development. However, previous studies have only been performed with transformed or immortalised cell lines. It remains unclear whether healthy primary colon epithelial cells respond the same way.

Cancer transformation

In this study, published in Nature Communications, researchers developed primary cell culture models derived from normal murine colon epithelial cells. They infected organoids and polarised monolayers from primary colon epithelial cells with pks+ E. coli or an isogenic mutant that is defective for colibactin synthesis. This allowed the team to induce changes that are characteristic of CRC. This included enhanced proliferation, Wnt-independence and impaired differentiation. Sequence analysis of these Wnt-independent organoids revealed an enhanced mutational burden. Surprisingly, the team did not observe mutations in genes directly involved in Wnt signalling, instead they found mutations related to p53 signalling. This supports the idea of a functional interplay between the p53 and Wnt pathways.

While these transformed cells did not exhibit the typical colibactin mutational signature, the new findings suggest that improper repair of colibactin-induced crosslinks can lead to several chromosomal aberrations. These aberrations are sufficient to cause primary cell transformation. Therefore, the team suggest that the transforming capacity of colibactin-producing E. coli may be higher than what is estimated from the presence of the mutational signature alone.

Photo by CDC on Unsplash

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Bacteria / Colon Cancer / Organoids