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

Mathijs P. Verhagen; Rosalie Joosten; Mark Schmitt; Niko Vaelimaeki; Andrea Sacchetti; Kristiina Rajamaeki; 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 Vaelimaeki, Andrea Sacchetti, Kristiina Rajamaeki, 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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
Pages (from-to)	1456-1467
Number of pages	12
Journal	Nature Genetics
Volume	56
Issue number	7
Early online date	20 Jun 2024
DOIs	https://doi.org/10.1038/s41588-024-01801-y
Publication status	Published - Jul 2024

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Publisher Copyright:
© The Author(s) 2024.

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Verhagen, M. P., Joosten, R., Schmitt, M., Vaelimaeki, N., Sacchetti, A., Rajamaeki, 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

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

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.",

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

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doi = "10.1038/s41588-024-01801-y",

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Verhagen, MP , Joosten, R, Schmitt, M, Vaelimaeki, N, Sacchetti, A, Rajamaeki, 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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AU - Verhagen, Mathijs P.

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AU - Schmitt, Mark

AU - Vaelimaeki, Niko

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AU - Rajamaeki, Kristiina

AU - Choi, Jiahn

AU - Procopio, Paola

AU - Silva, Sara

AU - van der Steen, Berdine

AU - van den Bosch, Thierry P. P.

AU - Seinstra, Danielle

AU - de Vries, Annemarie C.

AU - Doukas, Michail

AU - Augenlicht, Leonard H.

AU - Aaltonen, Lauri A.

AU - Fodde, Riccardo

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

Abstract

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