Psychological stress-induced ALKBH5 deficiency promotes tumour innervation and pancreatic cancer progression via extracellular vesicle transfer of m6A-modified RNAs. Psychological stress-induced ALKBH5 deficiency promotes tumour innervation and pancreatic cancer progression via extracellular vesicle transfer of m6A-modified RNAs

Pathological role and the 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 via stimulating tumor nerve innervation. We demonstrate that nociception and other stressors activate sympathetic nerve to release Noradrenaline, downregulating tumor cell RNA demethylase alkB homolog 5 (Alkbh5). Alkbh5 deficiency causes cancer cell aberrant m6A modification of RNAs, which are packed to extracellular vesicles and delivered to neurons in the tumor microenvironment, enhancing hyperinnervation and PDAC progression. ALKBH5 levels are reversely correlated with tumor innervation and survival time in PDAC patients. Animal experiments identify a natural flavonoid Fisetin preventing neurons from taking in m6A-RNA contained EVs and suppress PDAC tumor excessive innervation and progression. Together, our study shed light on a novel molecular mechanism for neuro-cancer crosstalk linking psychological stress and cancer progression and raise a potential strategy for PDAC therapy. Overall design: Chromatin immunoprecipitation DNA-sequencing ( ChIP-seq ) for H3K27ac and Chd4 in KPC cells

心理应激在癌症进展中的病理作用与调控机制迄今尚未明确。本研究通过小鼠模型证实，心理应激可通过激活肿瘤神经支配，促进胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）的进展。本研究证实，痛觉感受及其他应激源可激活交感神经释放去甲肾上腺素，下调肿瘤细胞内RNA去甲基化酶alkB同源物5（Alkbh5）的表达。Alkbh5缺失会导致肿瘤细胞内RNA出现异常的m⁶A修饰，此类修饰后的RNA被包裹进入细胞外囊泡（extracellular vesicles, EVs），并被递送至肿瘤微环境中的神经元，进而促进神经过度支配与PDAC进展。PDAC患者体内ALKBH5的表达水平与肿瘤神经支配程度呈负相关，与患者生存时间呈正相关。动物实验证实，天然黄酮类化合物非瑟酮（Fisetin）可阻断神经元摄取携带m⁶A修饰RNA的细胞外囊泡，进而抑制PDAC的过度神经支配与肿瘤进展。综上，本研究阐明了连接心理应激与癌症进展的神经-肿瘤串扰新分子机制，并为PDAC治疗提供了潜在策略。实验整体设计：针对KPC细胞中的组蛋白H3赖氨酸27乙酰化（H3K27ac）与染色质解旋酶DNA结合蛋白4（Chd4）开展染色质免疫共沉淀测序（Chromatin immunoprecipitation DNA-sequencing, ChIP-seq）。