Patients with mesenchymal tumours and high Fusobacteriales prevalence have worse prognosis in colorectal cancer (CRC).
Patients with mesenchymal tumours and high Fusobacteriales prevalence have worse prognosis in colorectal cancer (CRC).
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DOI：
10.1136/gutjnl-2021-325193
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发表时间：
2022-08
期刊：
影响因子：
24.5
通讯作者：
Prehn, Jochen H. M.
中科院分区：
文献类型：
--
作者：
Salvucci, Manuela;Crawford, Nyree;Stott, Katie;Bullman, Susan;Longley, Daniel B.;Prehn, Jochen H. M.
基于转录组学的亚型、共有分子亚型（CMS）和结直肠癌内在亚型（CRIS）鉴定具有间充质性状（CMS 4/CRIS-B）和较差结果的患者亚群。在这里，我们调查了具核梭杆菌（Fn）和梭杆菌目的患病率，CMS/CRIS亚型，细胞类型组成，免疫浸润和宿主环境之间的关系，以完善患者分层，并确定可药用的特定环境的脆弱性。我们将细胞培养实验与来自两个独立的结直肠癌患者队列的肿瘤中Fn/梭杆菌目患病率和宿主生物学/微环境的表征相结合（分类：n=140，癌症基因组图谱（TCGA-COAD-READ）队列的结肠和直肠病例：n=605）。在体外，Fn感染通过激活的B细胞的核因子κ轻链增强子/肿瘤坏死因子α在HCT 116和HT 29癌细胞系中诱导炎症。在患者中，在CMS 1、微卫星不稳定（）肿瘤中发现高Fn/梭杆菌目，伴有M1巨噬细胞浸润、M2巨噬细胞减少和高白细胞介素（IL）-6/IL-8/IL-1β信号传导。分类学队列的分析表明，Fn是CMS 4/CRIS-B患者的预后指标，尽管Fn负荷低于CMS 1患者。在TCGA-COAD-READ队列中，我们同样鉴定了当将患者分层为间充质（CMS 4和/或CRIS-B）与非间充质（既不是CMS 4也不是CRIS-B）时梭杆菌目相对丰度与结果之间的差异关联。间叶肿瘤和高梭杆菌的患者有大约两倍的风险更糟的结果。这些关联在非间质细胞患者中为零。用Logistic模型对梭杆菌目流行率、分子亚型和宿主环境之间的三向关联进行建模，其中相互作用项解开了病原体-宿主信号传导关系，并将畸变（包括NOTCH、CSF 1 -3和IL-6/IL-8）鉴定为候选靶标。本研究将具有高Fn/梭杆菌目患病率的CMS 4/CRIS-B患者确定为可能受益于靶向间充质生物学的治疗的高风险亚群。
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. 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). 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. 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.
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影响因子：
4.6
作者：
Allen WL;Dunne PD;McDade S;Scanlon E;Loughrey M;Coleman H;McCann C;McLaughlin K;Nemeth Z;Syed N;Jithesh P;Arthur K;Wilson R;Coyle V;McArt D;Murray GI;Samuel L;Nuciforo P;Jimenez J;Argiles G;Dienstmann R;Tabernero J;Messerini L;Nobili S;Mini E;Sheahan K;Ryan E;Johnston PG;Van Schaeybroeck S;Lawler M;Longley DB
通讯作者：
Longley DB
影响因子：
7
作者：
Castellarin, Mauro;Warren, Rene L.;Holt, Robert A.
通讯作者：
Holt, Robert A.
影响因子：
16.6
作者：
Isella C;Brundu F;Bellomo SE;Galimi F;Zanella E;Porporato R;Petti C;Fiori A;Orzan F;Senetta R;Boccaccio C;Ficarra E;Marchionni L;Trusolino L;Medico E;Bertotti A
通讯作者：
Bertotti A
使用合并的MAS 1HNMR和metataxonomic策略对结直肠癌中粘膜微生物组 - 米组组相互作用进行了前瞻性分析。
影响因子：
4.6
作者：
Kinross J;Mirnezami R;Alexander J;Brown R;Scott A;Galea D;Veselkov K;Goldin R;Darzi A;Nicholson J;Marchesi JR
通讯作者：
Marchesi JR
影响因子：
8
作者：
Green, Darrell;Eyre, Heather;Finegan, Katherine G.
通讯作者：
Finegan, Katherine G.