Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation

Mathijs P. Verhagen; Rosalie Joosten; Mark Schmitt; Niko Välimäki; Andrea Sacchetti; Kristiina Rajamäki; Jiahn Choi; Paola Procopio; Sara Silva; Berdine van der Steen; Thierry P.P. van den Bosch; Danielle Seinstra; Annemarie C. de Vries; Michail Doukas; Leonard H. Augenlicht; Lauri A. Aaltonen; Riccardo Fodde

doi:10.1038/s41588-024-01801-y

Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation

Mathijs P. Verhagen, Rosalie Joosten, Mark Schmitt, Niko Välimäki, Andrea Sacchetti, Kristiina Rajamäki, Jiahn Choi, Paola Procopio, Sara Silva, Berdine van der Steen, Thierry P.P. van den Bosch, Danielle Seinstra, Annemarie C. de Vries, Michail Doukas, Leonard H. Augenlicht, Lauri A. Aaltonen, Riccardo Fodde

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Abstract

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.

Original language	English (US)
Pages (from-to)	1456-1467
Number of pages	12
Journal	Nature Genetics
Volume	56
Issue number	7
DOIs	https://doi.org/10.1038/s41588-024-01801-y
State	Published - Jul 2024

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41588-024-01801-y

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Verhagen, M. P., Joosten, R., Schmitt, M., Välimäki, N., Sacchetti, A., Rajamäki, K., Choi, J., Procopio, P., Silva, S., van der Steen, B., van den Bosch, T. P. P., Seinstra, D., de Vries, A. C., Doukas, M., Augenlicht, L. H., Aaltonen, L. A., & Fodde, R. (2024). Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation. Nature Genetics, 56(7), 1456-1467. https://doi.org/10.1038/s41588-024-01801-y

Verhagen, MP, Joosten, R, Schmitt, M, Välimäki, N, Sacchetti, A, Rajamäki, K, Choi, J, Procopio, P, Silva, S, van der Steen, B, van den Bosch, TPP, Seinstra, D, de Vries, AC, Doukas, M, Augenlicht, LH, Aaltonen, LA & Fodde, R 2024, 'Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation', Nature Genetics, vol. 56, no. 7, pp. 1456-1467. https://doi.org/10.1038/s41588-024-01801-y

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abstract = "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.",

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AU - Silva, Sara

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AU - Seinstra, Danielle

AU - de Vries, Annemarie C.

AU - Doukas, Michail

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Non-stem cell lineages as an alternative origin of intestinal tumorigenesis in the context of inflammation

Abstract

ASJC Scopus subject areas

UN SDGs

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