2. Academic Validation
  3. Psychological stress-induced ALKBH5 deficiency promotes tumour innervation and pancreatic cancer via extracellular vesicle transfer of RNA

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

  • Nat Cell Biol. 2025 Jun;27(6):1035-1047. doi: 10.1038/s41556-025-01667-0.
Ziming Chen # 1,  Yifan Zhou # 1,  Chunling Xue # 1,  Lingxing Zeng 1,  Shuang Deng 1,  Zilan Xu 1,  Mei Li 2,  Hongzhe Zhao 1,  Xiaowei He 1,  Shaoqiu Liu 1,  Ji Liu 1,  Shuang Liu 1,  Sihan Zhao 1,  Shaoping Zhang 1,  Xinyi Peng 1,  Xiaoyu Wu 1,  Ruihong Bai 1,  Lisha Zhuang 1,  Shaojia Wu 1,  Jialiang Zhang 1,  Dongxin Lin 3 4 5,  Xudong Huang 6,  Jian Zheng 7 8 9
Affiliations

Affiliations

  • 1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
  • 2 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. lindx@cicams.ac.cn.
  • 4 Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. lindx@cicams.ac.cn.
  • 5 Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. lindx@cicams.ac.cn.
  • 6 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. huangxd@sysucc.org.cn.
  • 7 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. zhengjian@sysucc.org.cn.
  • 8 Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. zhengjian@sysucc.org.cn.
  • 9 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China. zhengjian@sysucc.org.cn.
  • # Contributed equally.
PMID: 40419796 DOI: 10.1038/s41556-025-01667-0
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.

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