Perineural invasion (PNI) is a biological characteristic commonly observed in pancreatic cancer. Although PNI plays a key role in pancreatic cancer metastasis, recurrence, and poor postoperative survival, its mechanism is largely unclarified. Clinical sample analysis and endoscopic ultrasonographic elasticity scoring indicated that cancer-associated fibroblasts (CAFs) were closely related to the occurrence of PNI. Furthermore, CAF-derived extracellular vesicles (EVs) were involved in PNI in dorsal root ganglion coculture and mouse sciatic nerve models. Next, we demonstrated that CAFs promoted PNI through extracellular vesicle transmission of PNI-associated transcript (PIAT). Mechanistically, PIAT specifically bound to YBX1 and blocked the YBX1-Nedd4l interaction to inhibit YBX1 ubiquitination and degradation. Furthermore, PIAT enhanced the binding of YBX1 and PNI-associated mRNAs in a 5-methylcytosine (m5C)–dependent manner. Mutation of m5C recognition motifs in YBX1 or m5C sites in downstream target genes reversed PIAT-mediated PNI. Consistent with these findings, analyses using a KPC mouse model demonstrated that the PIAT/YBX1 axis enhanced PNI through m5C modification. Clinical data suggested that the PIAT expression in the serum EVs of patients with pancreatic cancer was associated with the degree of neural invasion and prognosis. Our study revealed the important role of the PIAT/YBX1 signaling axis in the tumor microenvironment (TME) in promoting tumor cell PNI and provided a new target for precise interference with CAFs and RNA methylation in the TME to suppress PNI in pancreatic cancer.

中文翻译：

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来自癌症相关成纤维细胞的细胞外囊泡包装的 PIAT 通过介导胰腺癌小鼠模型中的 m5C 修饰来驱动神经重塑


神经周围浸润（PNI）是胰腺癌中常见的生物学特征。尽管 PNI 在胰腺癌转移、复发和术后生存不良中发挥着关键作用，但其机制在很大程度上尚不清楚。临床样本分析和内镜超声弹性评分表明癌相关成纤维细胞（CAFs）与PNI的发生密切相关。此外，CAF 衍生的细胞外囊泡 (EV) 参与背根神经节共培养和小鼠坐骨神经模型中的 PNI。接下来，我们证明 CAF 通过 PNI 相关转录物 (PIAT) 的细胞外囊泡传递来促进 PNI。从机制上讲，PIAT 特异性结合 YBX1 并阻断 YBX1-Nedd4l 相互作用，从而抑制 YBX1 泛素化和降解。此外，PIAT 以 5-甲基胞嘧啶 (m5C) 依赖性方式增强 YBX1 和 PNI 相关 mRNA 的结合。下游靶基因 YBX1 或 m5C 位点中 m5C 识别基序的突变可逆转 PIAT 介导的 PNI。与这些发现一致的是，使用 KPC 小鼠模型进行的分析表明，PIAT/YBX1 轴通过 m5C 修饰增强了 PNI。临床数据提示胰腺癌患者血清EVs中PIAT的表达与神经侵犯程度及预后相关。我们的研究揭示了肿瘤微环境（TME）中PIAT/YBX1信号轴在促进肿瘤细胞PNI中的重要作用，并为精确干扰TME中的CAF和RNA甲基化以抑制胰腺癌中的PNI提供了新的靶点。