Patients with mesenchymal tumours and highFusobacterialesprevalence have worse prognosis in colorectal cancer (CRC)

Abstract

ObjectivesTranscriptomic-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.DesignWe 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).ResultsIn 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.ConclusionThis study identifies CMS4/CRIS-B patients with high Fn/Fusobacteriales prevalence as a high-risk subpopulation that may benefit from therapeutics targeting mesenchymal biology.

Salivary Fusobacterium nucleatum serves as a potential biomarker for colorectal cancer

“…Existing data support that there is a positive relationship between the level of tissue Fn and worse prognosis in gastroenterological cancers, particularly CRC ( Mima et al., 2016 ; Salvucci et al., 2021 ; Yamaoka et al., 2018 ), esophageal cancer ( Yamamura et al., 2016 ), and gastric cancer ( Boehm et al., 2020 ). A recent meta-analysis also predicts that high levels of Fn in tumor tissues suggest a poor prognosis ( Huangfu et al., 2021 ).…”

Subchronic Toxicity of Microcystin-LR on Young Frogs (Xenopus laevis) and Their Gut Microbiota

“…An increase in the abundance of Desulfovibrio is closely related to metabolic diseases ( Petersen et al, 2019 ). Fusobacterium induced inflammation through TNF-α and NF-κB in an in vitro cultured colorectal cancer cell line ( Salvucci et al, 2021 ). In steatosis, steatohepatitis, and hepatocellular carcinoma, the abundance of Mucispirillum increases with an increase in the degree of inflammation ( Zhang et al, 2021 ).…”

Fusobacterium nucleatum induces pancreatic cancer cell proliferation and migration by regulating host autocrine and paracrine signaling

“…In fact, GM-CSF is known to activate MAPK and NFκB signaling in other cell types 53,65,66 . In CRC, it was identified that patients with mesenchymal tumors with Fusobacteria have a worse prognosis than patients with a more epithelial subtype 35 . Future work should therefore also investigate F. nucleatum impact based on the context of the genomic constitution or molecular subtype of pancreatic cancer [67][68][69] .…”

“…In addition, the adhesin FadA has been shown to bind to E-cadherin, which activates β-catenin and stimulates downstream signaling that promotes carcinogenesis 34 . However, there is still a critical knowledge gap in our understanding of how F. nucleatum adapts to the TME or continues to influence cancer phenotypes once colonizing the TME, to exacerbate the aggressiveness of both early and late-stage cancers 35 . Moreover, it has been shown that F. nucleatum may travel within the primary cells to distant tumor metastatic sites 36 and could contribute to pre-metastatic niche formation.…”