PT  - JOURNAL ARTICLE
AU  - Manuela Salvucci
AU  - Nyree Crawford
AU  - Katie Stott
AU  - Susan Bullman
AU  - Daniel B Longley
AU  - Jochen H M Prehn
TI  - Patients with mesenchymal tumours and high <em>Fusobacteriales</em> prevalence have worse prognosis in colorectal cancer (CRC)
AID  - 10.1136/gutjnl-2021-325193
DP  - 2022 Aug 01
TA  - Gut
PG  - 1600--1612
VI  - 71
IP  - 8
4099  - http://gut.bmj.com/content/71/8/1600.short
4100  - http://gut.bmj.com/content/71/8/1600.full
SO  - Gut2022 Aug 01; 71
AB  - Objectives Transcriptomic-based subtyping, consensus molecular subtyping (CMS) and colorectal cancer intrinsic subtyping (CRIS) identify a patient subpopulation with mesenchymal traits (CMS4/CRIS-B) and poorer outcome. Here, we investigated the relationship between prevalence of Fusobacterium nucleatum (Fn) and Fusobacteriales, CMS/CRIS subtyping, cell type composition, immune infiltrates and host contexture to refine patient stratification and to identify druggable context-specific vulnerabilities.Design We coupled cell culture experiments with characterisation of Fn/Fusobacteriales prevalence and host biology/microenviroment in tumours from two independent colorectal cancer patient cohorts (Taxonomy: n=140, colon and rectal cases of The Cancer Genome Atlas (TCGA-COAD-READ) cohort: n=605).Results In vitro, Fn infection induced inflammation via nuclear factor kappa-light-chain-enhancer of activated B cells/tumour necrosis factor alpha in HCT116 and HT29 cancer cell lines. In patients, high Fn/Fusobacteriales were found in CMS1, microsatellite unstable () tumours, with infiltration of M1 macrophages, reduced M2 macrophages, and high interleukin (IL)-6/IL-8/IL-1β signalling. Analysis of the Taxonomy cohort suggested that Fn was prognostic for CMS4/CRIS-B patients, despite having lower Fn load than CMS1 patients. In the TCGA-COAD-READ cohort, we likewise identified a differential association between Fusobacteriales relative abundance and outcome when stratifying patients in mesenchymal (either CMS4 and/or CRIS-B) versus non-mesenchymal (neither CMS4 nor CRIS-B). Patients with mesenchymal tumours and high Fusobacteriales had approximately twofold higher risk of worse outcome. These associations were null in non-mesenchymal patients. Modelling the three-way association between Fusobacteriales prevalence, molecular subtyping and host contexture with logistic models with an interaction term disentangled the pathogen–host signalling relationship and identified aberrations (including NOTCH, CSF1-3 and IL-6/IL-8) as candidate targets.Conclusion This study identifies CMS4/CRIS-B patients with high Fn/Fusobacteriales prevalence as a high-risk subpopulation that may benefit from therapeutics targeting mesenchymal biology.Data are available in a public, open access repository. Processing and analysis code along with bacterium estimates with corresponding clinical and molecular datasets for the Taxonomy and TCGA-COAD-READ cohorts included in this study are publicly available and archived at Zenodo (https://10.5281/zenodo.4019142). Bacterium estimates include Fusobacterium nucleatum load (Taxonomy cohort) and Fusobacteriales relative abundance, along with higher resolution estimates at genus, family and species taxonomic ranks, (TCGA-COAD-READ cohort).