Chen Ziming, Zhou Yifan, Xue Chunling, Zeng Lingxing, Deng Shuang, Xu Zilan, Li Mei, Zhao Hongzhe, He Xiaowei, Liu Shaoqiu, Liu Ji, Liu Shuang, Zhao Sihan, Zhang Shaoping, Peng Xinyi, Wu Xiaoyu, Bai Ruihong, Zhuang Lisha, Wu Shaojia, Zhang Jialiang, Lin Dongxin, Huang Xudong, Zheng Jian
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Nat Cell Biol. 2025 May 26. doi: 10.1038/s41556-025-01667-0.
The pathological role and mechanism of psychological stress in cancer progression are little known. Here we show in a mouse model that psychological stress drives pancreatic ductal adenocarcinoma (PDAC) progression by stimulating tumour nerve innervation. We demonstrate that nociception and other stressors activate sympathetic nerves to release noradrenaline, downregulating RNA demethylase alkB homologue 5 (Alkbh5) in tumour cells. Alkbh5 deficiency in these cancer cells causes aberrant N-methyladenosine (mA) modification of RNAs, which are packed into extracellular vesicles and delivered to nerves in the tumour microenvironment, enhancing hyperinnervation and PDAC progression. ALKBH5 levels are inversely correlated with tumour innervation and survival time in patients with PDAC. Animal experiments identify a natural flavonoid, fisetin, that prevents neurons from taking in extracellular vesicles containing mA-modified RNAs, thus suppressing the excessive innervation and progression of PDAC tumours. Our study sheds light on a molecular mechanism by which crosstalk between the neuroendocrine system and cancer cells links psychological stress and cancer progression and raises a potential strategy for PDAC therapy.
心理压力在癌症进展中的病理作用和机制鲜为人知。在此，我们在小鼠模型中表明，心理压力通过刺激肿瘤神经支配来驱动胰腺导管腺癌（PDAC）进展。我们证明伤害感受和其他应激源激活交感神经以释放去甲肾上腺素，从而下调肿瘤细胞中的RNA去甲基化酶alkB同源物5（Alkbh5）。这些癌细胞中Alkbh5的缺乏导致RNA的异常N-甲基腺苷（mA）修饰，这些RNA被包装到细胞外囊泡中并传递到肿瘤微环境中的神经，增强神经支配和PDAC进展。在PDAC患者中，ALKBH5水平与肿瘤神经支配和生存时间呈负相关。动物实验确定了一种天然黄酮类化合物非瑟酮，它可防止神经元摄取含有mA修饰RNA的细胞外囊泡，从而抑制PDAC肿瘤的过度神经支配和进展。我们的研究揭示了一种分子机制，通过该机制神经内分泌系统与癌细胞之间的串扰将心理压力与癌症进展联系起来，并提出了一种PDAC治疗的潜在策略。
