Keystone pathobionts associated with colorectal cancer promote oncogenic reprograming.
Keystone pathobionts associated with colorectal cancer promote oncogenic reprograming.
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与结直肠癌相关的关键致病生物促进致癌重编程。
DOI：
10.1101/2023.04.03.535410
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Brito,IlanaL
中科院分区：
文献类型：
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作者：
Jones,Josh;Shi,Qiaojuan;Nath,RahulR;Brito,IlanaL
核梭杆菌(FN)和脆性肠毒素杆菌(ETBF)是两种致病菌，与健康人相比，在结直肠癌患者的肠道菌群中持续丰富，并经常被观察到它们在肿瘤内的直接联系。虽然已经确定了几种分子机制，直接将这些微生物与特定细胞类型中的结直肠癌特征联系起来，但它们对上皮和局部免疫隔间的特定作用尚不清楚。为了填补这一空白，我们在野生型小鼠和结直肠癌小鼠模型上利用单细胞RNA测序(scRNA-seq)。我们发现，在结直肠癌小鼠模型中，FN和ETBF加剧了转运放大和成熟的肠细胞中的癌样转录表型。我们还观察到暴露于病原体的小鼠T细胞增加，但在野生型小鼠中观察到的这些病原体特异性差异在结直肠癌小鼠模型中被取消。尽管每种生物引起的反应有相似之处，但我们发现在Myc信号和脂肪酸代谢中有病原体特有的效应。这些发现支持FN和ETBF通过诱导肿瘤干细胞样转运放大和肠细胞群以及破坏CTL细胞毒功能而在促进肿瘤发生中的作用。
Fusobacterium nucleatum(Fn) and enterotoxigenicBacteroides fragilis(ETBF) are two pathobionts consistently enriched in the gut microbiomes of patients with colorectal cancer (CRC) compared to healthy counterparts and frequently observed for their direct association within tumors. Although several molecular mechanisms have been identified that directly link these organisms to features of CRC in specific cell types, their specific effects on the epithelium and local immune compartment are not well-understood. To fill this gap, we leveraged single-cell RNA sequencing (scRNA-seq) on wildtype mice and mouse model of CRC. We find that Fn and ETBF exacerbate cancer-like transcriptional phenotypes in transit-amplifying and mature enterocytes in a mouse model of CRC. We also observed increased T cells in the pathobiont-exposed mice, but these pathobiont-specific differences observed in wildtype mice were abrogated in the mouse model of CRC. Although there are similarities in the responses provoked by each organism, we find pathobiont-specific effects in Myc-signaling and fatty acid metabolism. These findings support a role for Fn and ETBF in potentiating tumorigenesis via the induction of a cancer stem cell-like transit-amplifying and enterocyte population and the disruption of CTL cytotoxic function.