Intestinal stem cells are crucial for maintaining intestinal homeostasis, yet their transformation into tumor stem cells in the context of microbial infection remains poorly understood. Fusobacterium nucleatum (F. nucleatum) is frequently associated with the onset and progression of colorectal cancer (CRC). In this study, we uncovered that F. nucleatum colonized the depths of gut crypts in both human CRC patients and mouse models. Through single-cell sequencing analysis, we demonstrated that F. nucleatum infection reprogrammed crypt cells and activated LY6A+ revival stem cells (RSCs), promoting their hyperproliferation and subsequent transformation into tumor stem cells, which accelerated intestinal carcinogenesis. Mechanistically, we identified LY6A as a GPI-anchored membrane receptor for F. nucleatum. Upon binding, F. nucleatum induced upregulation of RPS14 via the LY6A receptor, driving RSC hyperactivity and tumorigenic conversion. Functional studies showed that genetic ablation of Ly6a in intestinal epithelial cells or Rps14 in LY6A+ RSCs substantially reduced F. nucleatum colonization and tumorigenesis. Moreover, clinical CRC cohorts analysis revealed a strong correlation between F. nucleatum infection, RSC expansion, and elevated RPS14 expression in tumor tissues. These findings highlight an alternative F. nucleatum-LY6A-RPS14 signaling axis as a critical driver of CRC progression and propose potential therapeutic targets for effective CRC intervention.

中文翻译：

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Nucleatum 梭杆菌通过肿瘤干细胞的新生促进结直肠癌。


肠道干细胞对于维持肠道稳态至关重要，但在微生物感染的情况下，它们转化为肿瘤干细胞仍然知之甚少。有核梭杆菌 （F. nucleatum） 通常与结直肠癌 （CRC） 的发生和进展有关。在这项研究中，我们发现 F. nucleatum 在人类 CRC 患者和小鼠模型的肠道隐窝深处定植。通过单细胞测序分析，我们证明 F. nucleatum 感染重编程隐窝细胞并激活 LY6A+ 复兴干细胞 （RSC），促进其过度增殖并随后转化为肿瘤干细胞，从而加速肠道癌变。从机制上讲，我们确定 LY6A 是 F. nucleatum 的 GPI 锚定膜受体。结合后，F. nucleatum 通过 LY6A 受体诱导 RPS14 上调，驱动 RSC 多动和致瘤转化。功能研究表明，肠上皮细胞中 Ly6a 或 LY6A+ RSCs 中 Rps14 的遗传消融显着减少了 F. 核定植和肿瘤发生。此外，临床 CRC 队列分析显示，镰刀菌感染、RSC 扩增和肿瘤组织中 RPS14 表达升高之间存在很强的相关性。这些发现强调了另一种 F. nucleatum-LY6A-RPS14 信号轴是 CRC 进展的关键驱动因素，并提出了有效 CRC 干预的潜在治疗靶点。