中山大学郑健小组的一项最新研究发现了心理应激诱导的ALKBH5缺乏通过RNA的细胞外囊泡转移促进肿瘤神经支配和胰腺癌。2025年5月26日出版的《自然—细胞生物学》杂志发表了这项成果。

在本研究中，研究团队发现心理压力通过刺激肿瘤的神经支配来驱动胰腺导管腺癌（PDAC）的进展。研究小组证明，伤害感觉和其他应激源激活交感神经释放去甲肾上腺素，下调肿瘤细胞中RNA去甲基化酶Alkbh5 （Alkbh5）。这些癌细胞中Alkbh5的缺乏会引起N⁶-甲基腺苷（m⁶A）修饰RNA的异常，这些RNA被包装到细胞外囊泡中并在肿瘤微环境中传递给神经，从而增强神经亢进和PDAC的进展。在PDAC患者中，ALKBH5水平与肿瘤神经支配和生存时间呈负相关。动物实验发现，一种天然类黄酮非赛酮可以阻止神经元吸收含有m⁶A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。他们的研究揭示了神经内分泌系统和癌细胞之间的串扰将心理压力和癌症进展联系起来的分子机制，并提出了PDAC治疗的潜在策略。

据悉，心理应激在肿瘤进展中的病理作用和机制尚不清楚。

附：英文原文

Title: Psychological stress-induced ALKBH5 deficiency promotes tumour innervation and pancreatic cancer via extracellular vesicle transfer of RNA

Author: 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

Issue&Volume: 2025-05-26

Abstract: 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 N6-methyladenosine (m6A) 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 m6A-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.

DOI: 10.1038/s41556-025-01667-0

Source: https://www.nature.com/articles/s41556-025-01667-0