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Exosomal lncRNA XIST promotes perineural invasion of pancreatic cancer cells via miR-211-5p/GDNF

Oncogene (2024)Cite this article

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Abstract

Perineural invasion (PNI) is an essential form of tumor metastasis in multiple malignant cancers, such as pancreatic cancer, prostate cancer, and head and neck cancer. Growing evidence has revealed that pancreatic cancer recurrence and neuropathic pain positively correlate with PNI. Therefore, targeting PNI is a proper strategy for pancreatic cancer treatment. Exosomal lncRNA derived from pancreatic cancer cells is an essential component of the tumor microenvironment. However, whether exosomal lncXIST derived from pancreatic cancer cells can promote PNI and its exact mechanism remains to be elucidated. We show that lncXIST mediates nerve-tumor crosstalk via exosomal delivery. Our data reveal that exosomal lncXIST derived from pancreatic cancer cells is delivered to neural cells and promotes their release of glial-cell-line-derived neurotrophic factor (GDNF), essential in facilitating the PNI of pancreatic cancer. Mechanistically, microRNA-211-5p negatively regulates GDNF, and lncXIST serves as a miR-211-5p sponge. The function of exosomes in the dynamic interplay between nerves and cancer is confirmed in both in vivo and in vitro PNI models. Therefore, targeting pancreatic cancer cell-derived exosomal lncXIST may provide clues for a promising approach for developing a new strategy to combat PNI of pancreatic cancer.

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Fig. 1: Exosomes promoted PNI in pancreatic cancer.
Fig. 2: Deficiency of exosomes blocked PNI of pancreatic cancer in vivo.
Fig. 3: Exosomal transport of lncXIST from pancreatic cancer cells to nerve cells induced PNI.
Fig. 4: Exosomal lncXIST increased neural cell secretion of GDNF, followed by activation of RET in pancreatic cancer cells.
Fig. 5: XIST/GDNF axis was closely related to mice’s PNI in pancreatic cancer.
Fig. 6: miR-211-5p directly binds to XIST and GDNF 3′-UTR.

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Data availability

The data underlying Fig. 3A–C are available in the GEO, ICGC and TCGA databases. All other data are available in the main text.

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Acknowledgements

This work was funded by Dalian municipal Dengfeng Clinical Medicine Grant Support (No. 2021024). We thank Dr. Paul. J. Chiao provided the murine pancreatic cancer KRAS/p53m/+ cell line from the pancreas of Pdx1-cre/KRASLSL-G12D/p53LSL-R273H mice.

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  1. These authors contributed equally: Ke Cheng, Jinjin Pan, Qinlong Liu.

Authors and Affiliations

  1. The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China

    Ke Cheng, Jinjin Pan, Qinlong Liu, Yuke Ji, Liang Liu, Jinyue Sun, Miaomiao Gong & Yuhui Yuan

  2. Institute of Biomedical Informatics, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Software, School of Basic Medical Sciences, Academy for Advanced Interdisciplinary Studies, Henan University, Kaifeng, 47500, China

    Xiangqian Guo & Qiang Wang

  3. College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China

    Shao Li

  4. Sixth Department of liver disease, Dalian Public Health Clinical Center, Dalian, 116044, China

    Ying Zhang

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Contributions

Ke Cheng, Miaomiao Gong, and Yuke Ji were responsible for conducting the research and investigation process, explicitly performing the experiments, collecting data, preparing figures, and writing the initial draft. Ke Cheng is also responsible for screening potentially eligible studies, extracting and analyzing data, interpreting results, and updating reference lists. Jinjin Pan and Yuhui Yuan were responsible for preparing and presenting the published work and oversight and leadership responsibility for the research. Qinlong Liu and Ying Zhang provided the acquisition of the financial support for the project. Liang Liu, Xiangqian Guo, and Qiang Wang are responsible for the application of statistical, mathematical, computational, and other formal techniques to analyze or synthesize study data. Shao Li is responsible for the creation of models.

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Correspondence to Miaomiao Gong, Ying Zhang or Yuhui Yuan.

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Cheng, K., Pan, J., Liu, Q. et al. Exosomal lncRNA XIST promotes perineural invasion of pancreatic cancer cells via miR-211-5p/GDNF. Oncogene (2024). https://doi.org/10.1038/s41388-024-02994-6

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