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

Sep 21, 2026

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Conventional views link colon cancer to stem cells, yet inflammation can suppress intestinal stemness. This study uses Paneth cells in mice to test whether differentiated lineages can initiate tumors during inflammation. Paneth cell–specific Apc mutations produce intestinal tumors resembling those in inflammatory bowel disease and a larger share of human sporadic colon cancers. Machine learning analysis of patient-derived samples supports secretory-lineage origins in a substantial fraction of sporadic cases, implicating inflammation-driven cellular reprogramming.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages34

Reading Time1 h 26 min

AccessFree to download

Introduction

Paneth cells as a model for cell-of-origin

Experimental strategy for inflammation-driven tumorigenesis

Tumor outcomes and molecular characterization

Computational confirmation using patient-derived tumor samples

nature genetics Article [https://doi.org/10.1038/s41588-024-01801-y](https://doi.org/10.1038/s41588-024-01801-y) Non-stem cell lineages asan alternative origin of intestinal tumorigenesis in the context of inflammation Received: 1 December 2023 Accepted: 15 May 2024 | Published online: 20 June 2024 | | --- | | Check for updates | Mathijs P. Verhagen 1, Rosalie Joosten1, Mark Schmitt1,2, Niko Välimäki 3,4, Andrea Sacchetti1, Kristiina Rajamäki 3,4, Jiahn Choi 5, Paola Procopio2, Sara Silva2, Berdinevan der Steen6, Thierry P. P. van den Bosch1, Danielle Seinstra1, Annemarie C. de Vries7, Michail Doukas 1, Leonard H. Augenlicht5, LauriA. Aaltonen 3,8 & Riccardo Fodde 1 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 asa 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 inpatients 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, ina substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineagesand not in stem cells. The origin of the vast majority of cancers is thought to reside in stem-like or progenitor-like cells, which satisfy the need for active proliferation, self-renewal and differentiation capacity1–3. This was demonstrated in the mouse intestine where loss-of-function mutationsintheApc tumor suppressor gene successfully initiate adenoma formation only when they occur in Lgr5+ intestinal stem cells (ISCs). When the same Apc mutation is introduced in more-committed and shorter-lived transit-amplifying cells, tumor formation is halted at early microadenoma stages2. However, in addition to this ‘bottom-up’scenario,‘top-down’models of intestinal tumorigenesis have been proposed in which more-committed intestinal cells located at higher positions along the crypt–villus axis are likely to initiate cancer, especially in the context of tissue injury and inflammation4,5. In the specific case of human colon cancer, western-style dietary habits and chronic inflammation, two of the major etiologic factors associated with increased risk for sporadic malignant disease in the digestive tract, are thought to induce specific cellular and molecular alterations in the intestinal epithelium that ultimately lead to the expansion of cell targets for tumor initiation and progression4,6. However, which specific cell lineages are capable of dedifferentiating upon tissue injury and which are the underlying mechanisms remain largely unclear. Paneth cells (PCs) are specialized secretory cells located atthe very bottom of the crypt of Lieberkühn inthe small intestine where they secrete antimicrobial peptides into the lumen7. Moreover, they provide 1Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands. 2Institute of Pharmacology, University of Marburg, Marburg, Germany. 3Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland. 4Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. 5Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA. 6Department of Otorhinolaryngology and Head & Neck Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands. 7Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands. 8iCAN Digital Precision Cancer Medic

FAQs

Why does the study challenge the conventional stem-cell origin model for colon cancer?

It addresses evidence that inflammation suppresses intestinal stemness, while inflammation is a major risk factor for colon cancer. The work evaluates whether differentiated lineages can instead trigger tumorigenesis under inflammatory conditions.

What experimental approach is used to test the role of Paneth cells?

The study uses a mouse Cre–lox lineage-specific targeting strategy to introduce Apc (and related oncogenic drivers in the design) in Paneth cells, with or without inflammatory stimulation using DSS. Tumorigenesis is then measured.

How did the researchers support their conclusions using human cancer data?

Machine learning methods predict the cell-of-origin from patient-derived tumor samples. Results indicate that in a substantial fraction of sporadic cases, origins lie in secretory lineages rather than stem cells.

Sep 21, 2026

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