神经周围浸润（PNI）是宫颈癌侵袭和转移的一种新途径，涉及肿瘤与神经之间的串扰。然而，PNI 的起始信号和细胞相互作用机制在很大程度上仍然难以捉摸。为改善术后生活质量而提出的保留神经根治性子宫切除术（NSRH）仅适用于无PNI的宫颈癌患者。因此，阐明 PNI 的潜在机制并提出在 NSRH 手术前预测 PNI 的有效生物标志物非常重要。在此，我们发现PNI是晚期宫颈癌的特征，雪旺细胞是启动PNI的先行细胞。此外，宫颈癌细胞产生的神经肽神经调节素 B (NMB) 被确定可通过重编程施万细胞来诱导 PNI，包括驱动其形态和转录变化，促进其增殖和迁移，并通过分泌 CCL2 和指导轴突再生来启动 PNI。从机制上讲，宫颈癌细胞产生的 NMB 激活雪旺细胞中的受体 NMBR，并打开 T 型钙通道，通过 PKA 信号传导刺激 Ca2+ 流入，而该信号可以被抑制剂阻断。临床上建议联合检测血清NMB和CCL2水平可以有效预测宫颈癌患者的PNI。我们的数据表明，宫颈癌产生的 NMB 启动施万细胞的重新编程，然后指导轴突再生，从而导致 PNI 发作。血清 NMB 和 CCL2 水平升高可能有助于宫颈癌患者子宫切除手术期间保留神经的决策。© 2024。作者。

Perineural invasion (PNI) is a new approach of cervical cancer invasion and metastasis, involving the cross-talk between tumor and nerve. However, the initiating signals and cellular interaction mechanisms of PNI remain largely elusive. The nerve-sparing radical hysterectomy (NSRH) proposed to improve postoperative quality of life is only applicable to cervical cancer patients without PNI. Therefore, it is important to elucidate the underlying mechanisms initiating PNI, and suggest the effective biomarkers to predict PNI before NSRH surgery. Here, we found that PNI is the characteristic of advanced cervical cancer, and Schwann cells were the antecedent cells that initiating PNI. Further, neuropeptide neuromedin B (NMB) produced by cervical cancer cells was determined to induce PNI by reprogramming Schwann cells, including driving their morphological and transcriptional changes, promoting their proliferation and migration, and initiating PNI by secreting CCL2 and directing axon regeneration. Mechanistically, cervical cancer cells-produced NMB activated its receptor NMBR in Schwann cells, and opened the T-type calcium channels to stimulate Ca2+ influx through PKA signaling, which could be blocked by the inhibitor. Clinically, combined examination of serum NMB and CCL2 levels was suggested to effectively predict PNI in cervical cancer patients. Our data demonstrate that cervical cancer-produced NMB initiates the reprograming of Schwann cells, which then direct axon regeneration, thus causing PNI onset. The elevated serum NMB and CCL2 levels may be useful for the decision-making to nerve sparing during hysterectomy surgery of cervical cancer patients.© 2024. The Author(s).