Microbial Invasion and Immunosuppression Drives Adenoma Progression in Early Colorectal Cancer Development
Year: 2026
Type: preprint
Abstract: Several inherited predispositions to colorectal cancer exist, most notably familial adenomatous polyposis (FAP), which typically involves a germline loss-of-function mutation in one APC allele. A second hit in APC or related loci leads to aberrant Wnt signalling, triggering adenoma formation with near-complete penetrance. Yet, substantial variability in disease onset and severity, even among siblings with identical APC germline mutations, implicates environmental modifiers. Emerging evidence points to the gut microbiome as a critical regulator of adenoma initiation and progression, particularly in early-onset CRC. Here, we show that bacterial invasion is associated with neutrophil immunosuppression, T-cell exclusion and adenoma progression in a porcine model of FAP. Longitudinal mapping of progressing and regressing polyps using single-cell RNA sequencing, spatial transcriptomics and integrated microbiome profiling resolved the cellular and microbial architecture underlying these divergent lesion states. Single-cell RNA-seq identified 35 cell subpopulations and showed that regressing polyps are enriched for central-memory CD4+ T cells, cytotoxic CD8+ T cells and inflammatory neutrophils, whereas progressing polyps contain immunosuppressive/PD-L1-associated neutrophils, regulatory and dysfunctional T cells. Spatial transcriptomics with a custom host panel and targeted bacterial probes linked bacterial-high adenomatous regions to immunosuppressive neutrophil niches and T cell exclusion, while regressing lesions showed predominantly lumen-adjacent bacterial localization and spatially organized immune surveillance. These results provide a spatially resolved map of cellular and microbial organisation in early colorectal polyp progression and regression and reveal a microbiome-driven, neutrophil-mediated mechanism of early tumour progression with implications for CRC interception.
Authors: Wei Liang, Lisa Falk, Daniele Lucarelli, Philipp Putze, Amira Metwaly, Yiran Zheng, Fabian Springer, Thomas Winogrodzki, Qixia Chan, Theresa M. Pauli, Yue Zhang, Georg Zeller, Matthias Meier, Angelika Schnieke, Friederike Ebner, Dirk Haller, Tatiana Flisikowska, Dieter Saur, Krzysztof Flisikowski
Institutions: Technical University of Munich, German Cancer Research Center, TUM Klinikum, Deutsches Konsortium für Translationale Krebsforschung, Helmholtz Munich, European Molecular Biology Laboratory, Columbia University Irving Medical Center, Leiden University Medical Center, Leipzig University, Poznań University of Life Sciences
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: Deutsche Forschungsgemeinschaft
OpenAlex ID: W7168149560