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Tumor innervation is triggered by endoplasmic reticulum stress

Oncogene volume 41, pages 586–599 (2022)Cite this article

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Abstract

Nerve infiltration in the tumor microenvironment is emerging as a promoter of cancer progression that could be targeted in therapies, but the mechanisms initiating tumor innervation remain to be elucidated. Here we report that endoplasmic reticulum (ER) stress in cancer cells is transmitted to neuronal cells, resulting in neurite outgrowth and tumor innervation. In vitro, the induction of ER stress in various human cancer cells resulted in the synthesis and release of the precursor for brain-derived neurotrophic factor (proBDNF) through a mechanism dependent on the transcription factor X-box binding protein 1 (XBP1). Cancer cell-released proBDNF was found to mediate the transmission of ER stress to neurons, resulting in the stimulation of neurite outgrowth. Next-generation sequencing indicated the increased expression of the Egl-9 family hypoxia inducible factor 3 (EGLN3) that was mediated by c-MYC and necessary to neurite outgrowth induced by proBDNF. In orthotopic tumor xenograft, ER stress stimulated XBP1 and proBDNF expression as well as tumor innervation. Anti-proBDNF antibody inhibited both tumor innervation and cancer progression induced by ER stress. Interestingly, the chemotherapeutic drug 5-Fluorouracil (5-FU) was found to induce ER stress and tumor innervation, and this effect was inhibited by anti-proBDNF antibody. Finally, in human tumors, cancer tissues with nerve infiltration expressed high XBP1 and proBDNF while EGLN3 was upregulated in infiltrated nerves. This study reveals that ER stress participates in tumor innervation through the release of proBDNF and that targeting this pathway could be used in future therapies.

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Fig. 1: Transmission of ER stress from cancer cells to neurons induces neurite outgrowth.
Fig. 2: Inhibition of transmissible tumor ER stress reduces neurite outgrowth.
Fig. 3: XBP1-mediated release of proBDNF by cancer cells is responsible for transmission of ER stress and neurite outgrowth.
Fig. 4: Upregulation of EGLN3 in neuronal cells mediates neurite outgrowth induced by ER-stressed cancer cells.
Fig. 5: c-MYC contributes to proBDNF-mediated EGLN3 upregulation.
Fig. 6: Targeting proBDNF in vivo prevents ER stress-induced tumor innervation.
Fig. 7: ER stress is associated with innervation in human tumors.
Fig. 8: The association between proBDNF, XBP1, EGLN3 and innervation in human tumors.
Fig. 9: Schematic illustration of the mechanism responsible for tumor ER stress-induced tumor innervation.

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Acknowledgements

This work was supported by the University of Newcastle (Australia), the Hunter Cancer Research Alliance, the Hunter Medical Research Institute, and the Maitland Cancer Appeal Committee (NSW Australia). We thank Kristen McEwan for excellent technical contribution. We also thank Kathryn Leaney from Cancer Voice NSW for her excellent consumer contribution.

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Author notes

  1. Fangfang Gao

    Present address: Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, PR China

Authors and Affiliations

  1. Cancer Neurobiology Group, School of Biomedical Sciences & Pharmacy, The University of Newcastle, Callaghan, NSW, 2308, Australia

    Chen Chen Jiang, Mark Marsland, Amiee Dowdell, Edward Eden, Fangfang Gao, Sam Faulkner, Phillip Jobling, Xiang Li & Hubert Hondermarck

  2. Hunter Medical Research Institute, New Lambton, NSW, 2305, Australia

    Chen Chen Jiang, Mark Marsland, Amiee Dowdell, Edward Eden, Fangfang Gao, Sam Faulkner, Phillip Jobling, Xiang Li & Hubert Hondermarck

  3. School of Medicine & Public Health, The University of Newcastle, Callaghan, NSW, 2308, Australia

    Chen Chen Jiang

  4. West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, PR China

    Yufang Wang, Lihua Liu & Zhangyu He

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Contributions

CCJ and HH outlined the study and prepared the paper with input from all co-authors. EE and MM performed the ELISA assays. CCJ, MM, AD, EE, and SF executed the IHC staining. CCJ, AD, EE, PJ, FG and XL completed all the other in vitro assays. YW, LL, and ZH carried out the animal work.

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Correspondence to Hubert Hondermarck.

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Jiang, C.C., Marsland, M., Wang, Y. et al. Tumor innervation is triggered by endoplasmic reticulum stress. Oncogene 41, 586–599 (2022). https://doi.org/10.1038/s41388-021-02108-6

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