Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation
Menée à l'aide de modèles murins, de méthodes d'apprentissage automatique et d'une analyse immunohistochimique d'échantillons tissulaires d'origine murine ou humaine, cette étude démontre que, dans un contexte inflammatoire, la tumorigenèse colorectale peut avoir pour origine des cellules autres que des cellules souches
According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells.
Nature Genetics , article en libre accès, 2024