A Distinct Host-Microbiome Signature Underlies the Accelerated Malignant Potential of Colorectal Laterally Spreading Tumors.

Authors

Tymofiy Lutsiv, Henry J Thompson, Oliver Fiehn, Melanie G Gareau, Alexander D Borowsky, Brian H Chen, Hisham Hussan

Published in

Gastro hep advances. Volume 5. Issue 12. Pages 101102. Epub Aug 21, 2026.

Abstract

Laterally spreading tumors (LST) are flat colorectal neoplasms with an accelerated risk of malignant transformation and interval colorectal cancer. Despite their clinical importance, the molecular and microbial mechanisms underlying LST's aggressive biology remain poorly understood. Thus, we aimed to characterize the transcriptomic and microbial landscape of LST in comparison with paired protruding lesions and the adjacent normal colonic tissue.
Formalin-fixed, paraffin-embedded tissues from 36 samples were obtained from 15 adults and analyzed using RNA sequencing and 16S rRNA gene amplicon sequencing. Patterns of the differential gene expression were assessed using Gene Set Enrichment Analysis and Ingenuity Pathway Analysis. Microbial community composition and its predicted functional capacity were evaluated with analysis of compositions of microbiomes with bias correction in QIIME 2 and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2, respectively.
Compared with paired protruding lesions and normal tissue, LST exhibited a distinct protumorigenic transcriptomic profile marked by the activation of MYC, E2F, mTOR, DNA damage, and senescence-associated secretory phenotype pathways, as well as robust proinflammatory signaling driven by TNF, NF-κB, IL-1, and IL-17. LST tissue also demonstrated a permissive environment for genomic instability. Microbiome analysis revealed enrichment of Fusobacterium and depletion of beneficial taxa, including Lactococcus, accompanied by predicted suppression of carbohydrate fermentation and short-chain fatty acid production, as well as altered sulfur metabolism. Fusobacterium abundance correlated with increased TNF expression, supporting a microbiota-driven inflammatory niche in LST.
LST are characterized by a unique inflammatory/metabolic/senescence axis that distinguishes them from other paired colorectal tissue samples. This procarcinogenic signature is driven by a Fusobacterium-enriched and carbohydrate-fermentation-depleted microbial ecosystem. These findings highlight the gut microbial ecosystem as a critical cofactor in LST pathogenesis and further support that combined host/microbiota-targeted strategies may improve colorectal cancer prevention in this population. Given the exploratory nature and limited cohort size, these findings require validation in larger prospective cohorts with metagenomic and metabolomic integration.

PMID:
42819443
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

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