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10.3390/cells15181685
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Review

Villous Architecture in Colorectal Adenomas: Molecular Pathogenesis, Epithelial Plasticity, and Malignant Risk

by
Zedong Hu
1,†,
Tristan Vanoverbeke
1,†,
Ke Yin
1,
Alexander Jans
2,3,
Chuanmei Carlotta Arpaia
4,
Raf Bisschops
2,3,
Paméla Baldin
5,
Sabine Tejpar
1,2 and
Hubert Piessevaux
4,*
1
Digestive Oncology, Department of Oncology, KU Leuven, 3000 Leuven, Belgium
2
Department of Gastroenterology and Hepatology, UZ Leuven, 3000 Leuven, Belgium
3
Department of Translational Research in Gastrointestinal Diseases (TARGID), KU Leuven, 3000 Leuven, Belgium
4
Department of Hepato-Gastroenterology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium
5
Department of Pathology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2026, 15(18), 1685; https://doi.org/10.3390/cells15181685
Submission received: 2 August 2026 / Revised: 12 September 2026 / Accepted: 15 September 2026 / Published: 17 September 2026
(This article belongs to the Special Issue Pathogenesis and Novel Therapies for Epithelial Carcinoma)
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Abstract

Villous morphology is routinely used to stratify risk in conventional colorectal adenomas, yet it remains largely interpreted as a visual histological descriptor. This review proposes a different view: villous architecture is a graded, spatially organized epithelial state that links premalignant tissue remodeling to malignant potential. Across histological, molecular, and microenvironmental studies, villous-containing adenomas show convergent features of WNT-driven stem-like expansion, YAP-associated plasticity, fetal-regenerative or fetal-metaplastic transcriptional programs, mucin remodeling, stromal activation, immune attenuation, and genomic instability. These features appear to arise through interacting routes rather than through a single deterministic mutation. This framework helps explain why villous proportion predicts risk imperfectly: it captures a composite biological state but does not resolve its individual components. Quantitative morphometry, spatial transcriptomics, multiplex imaging, and region-resolved genomics could therefore move villous architecture from an observer-dependent category to a continuous, biologically interpretable marker of early malignant transition. Such a shift may improve adenoma classification, refine surveillance strategies, and identify high-risk lesions before conventional thresholds for advanced histology are reached.
Keywords: colorectal adenoma; villous architecture; epithelial plasticity; YAP; colorectal carcinogenesis colorectal adenoma; villous architecture; epithelial plasticity; YAP; colorectal carcinogenesis

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MDPI and ACS Style

Hu, Z.; Vanoverbeke, T.; Yin, K.; Jans, A.; Arpaia, C.C.; Bisschops, R.; Baldin, P.; Tejpar, S.; Piessevaux, H. Villous Architecture in Colorectal Adenomas: Molecular Pathogenesis, Epithelial Plasticity, and Malignant Risk. Cells 2026, 15, 1685. https://doi.org/10.3390/cells15181685

AMA Style

Hu Z, Vanoverbeke T, Yin K, Jans A, Arpaia CC, Bisschops R, Baldin P, Tejpar S, Piessevaux H. Villous Architecture in Colorectal Adenomas: Molecular Pathogenesis, Epithelial Plasticity, and Malignant Risk. Cells. 2026; 15(18):1685. https://doi.org/10.3390/cells15181685

Chicago/Turabian Style

Hu, Zedong, Tristan Vanoverbeke, Ke Yin, Alexander Jans, Chuanmei Carlotta Arpaia, Raf Bisschops, Paméla Baldin, Sabine Tejpar, and Hubert Piessevaux. 2026. "Villous Architecture in Colorectal Adenomas: Molecular Pathogenesis, Epithelial Plasticity, and Malignant Risk" Cells 15, no. 18: 1685. https://doi.org/10.3390/cells15181685

APA Style

Hu, Z., Vanoverbeke, T., Yin, K., Jans, A., Arpaia, C. C., Bisschops, R., Baldin, P., Tejpar, S., & Piessevaux, H. (2026). Villous Architecture in Colorectal Adenomas: Molecular Pathogenesis, Epithelial Plasticity, and Malignant Risk. Cells, 15(18), 1685. https://doi.org/10.3390/cells15181685

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