Microbial Invasion and Immunosuppression Drives Adenoma Progression in Early Colorectal Cancer Development
- 1Technical University of Munich
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.
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BibTeX
@misc{liang2026microbial,
title = {{Microbial Invasion and Immunosuppression Drives Adenoma Progression in Early Colorectal Cancer Development}},
author = {W. Liang and L. Falk and D. Lucarelli and P. Putze and A. Metwaly and Y. Zheng and F. Springer and T. Winogrodzki and Q. Chan and T. M. Pauli and Y. Zhang and G. Zeller and M. Meier and A. Schnieke and F. Ebner and D. Haller and T. Flisikowska and D. Saur and K. Flisikowski},
howpublished = {bioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.10.737736},
url = {https://www.biorxiv.org/content/10.64898/2026.07.10.737736v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Microbial Invasion and Immunosuppression Drives Adenoma Progression in Early Colorectal Cancer Development
AU - W. Liang
AU - L. Falk
AU - D. Lucarelli
AU - P. Putze
AU - A. Metwaly
AU - Y. Zheng
AU - F. Springer
AU - T. Winogrodzki
AU - Q. Chan
AU - T. M. Pauli
AU - Y. Zhang
AU - G. Zeller
AU - M. Meier
AU - A. Schnieke
AU - F. Ebner
AU - D. Haller
AU - T. Flisikowska
AU - D. Saur
AU - K. Flisikowski
PY - 2026
DA - 2026/07/10
PB - bioRxiv
DO - 10.64898/2026.07.10.737736
UR - https://www.biorxiv.org/content/10.64898/2026.07.10.737736v2
AB - 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.
ER -