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Cellular and Molecular Biology

Tumour-associated macrophages and Schwann cells promote perineural invasion via paracrine loop in pancreatic ductal adenocarcinoma

British Journal of Cancer volume 130, pages 542–554 (2024)Cite this article

Subjects

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by perineural invasion (PNI), which is associated with excruciating neuropathic pain and malignant progression. However, the relationship between PNI and tumour stromal cells has not been clarified.

Methods

The dorsal root ganglia or sciatic nerves nerve model was used to observe the paracrine interaction and the activation effect among Schwann cells, tumour-associated macrophages (TAMs), and pancreatic cancer cells in vitro. Next generation sequencing, enzyme-linked immunosorbent assay and chromatin immunoprecipitation were used to explore the specific paracrine signalling between TAMs and Schwann cells.

Results

We demonstrated that more macrophages were expressed around nerves that have been infiltrated by pancreatic cancer cells compared with normal nerves in murine and human PNI specimens. In addition, high expression of CD68 or GFAP is associated with an increased incidence of PNI and indicates a poor 5-year survival rate in patients with PDAC. Mechanistically, tumour-associated macrophages (TAMs) activate Schwann cells via the bFGF/PI3K/Akt/c-myc/GFAP pathway. Schwann cells secrete IL-33 to recruit macrophages into the perineural milieu and facilitate the M2 pro-tumourigenic polarisation of macrophages.

Conclusions

Our study demonstrates that the bFGF/IL-33 positive feedback loop between Schwann cells and TAMs is essential in the process of PNI of PDAC. The bFGF/PI3K/Akt/c-myc/GFAP pathway would open potential avenues for targeted therapy of PDAC.

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Fig. 1: Macrophage expression in murine and human perineural invasion samples.
Fig. 2: TAMs promote the migration and proliferation of Schwann cells.
Fig. 3: TAMs promote the activation of Schwann cells by upregulating the expression of GFAP.
Fig. 4: TAMs promote the activation of Schwann cells in vivo.
Fig. 5: TAMs activate Schwann cells by secreting factor bFGF.
Fig. 6: TAMs activate Schwann cells through bFGF/PI3K/Akt/c-myc/GFAP pathway.
Fig. 7: Loss of bFGF decreases perineural invasion in vivo.
Fig. 8: Clinicopathological correlation of GFAP and CD68 expression in human samples.

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Data availability

The data generated in this study are publicly available in Gene Expression Omnibus (GEO) at GSE194191 and GSE194205. Other supporting data are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank all study participants and their families for supporting our research.

Funding

This research was supported by grants from the Natural Science Foundation of China (82073149, 81672807, 82003073, 82203526), the Natural Science Foundation of Guangdong Province, China (No.2020A1515011296, 2020A1515111135, 2021A1515012357, 2022A1515220219), Guangdong Science and Technology Department (No.2020B1212060018), and Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004).

Author information

Author notes

  1. These authors contributed equally: Bin Zhang, Xiaofeng Guo, Leyi Huang.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, Guangdong, People’s Republic of China

    Bin Zhang, Leyi Huang, Longfa Lin, Peng Zhou, Huilin Ye, Yanan Lu & Quanbo Zhou

  2. Department of Pancreatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, Guangdong, People’s Republic of China

    Bin Zhang, Leyi Huang, Longfa Lin, Peng Zhou, Huilin Ye & Quanbo Zhou

  3. Department of General Surgery, Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 510655, Guangzhou, Guangdong, People’s Republic of China

    Bin Zhang

  4. Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, 510655, Guangzhou, Guangdong, People’s Republic of China

    Bin Zhang

  5. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, 510655, Guangzhou, Guangdong, People’s Republic of China

    Bin Zhang

  6. Center for medical research on innovation and translation, Institute of Clinical Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, 510180, Guangzhou, Guangdong, People’s Republic of China

    Xiaofeng Guo

  7. Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, 510655, Guangzhou, Guangdong, People’s Republic of China

    Yuting Zhang

  8. Department of thoracic surgery, The Second People’s Hospital, 528000, Foshan, Guangdong, People’s Republic of China

    Zhiguo Li

  9. Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, People’s Republic of China

    Dan Su

  10. Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, Guangdong, People’s Republic of China

    Yanan Lu

  11. Department of Pancreatic Surgery, Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 519041, Guangzhou, Guangdong, People’s Republic of China

    Quanbo Zhou

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  1. Bin Zhang
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Contributions

QZ and YL conceived of the study. BZ, XG, and HY experimented on the function and mechanisms and analysed the data. LH conducted the experiment, and analysed the data. BZ and LH revised the manuscript, and YZ, ZL, DS, LL, and PZ conducted the IHC assay. HY conceived of the study and guided the revision of manuscripts. The manuscript was written by QZ, BZ, XG, HY, LH, and YL. All authors made comments on the results and manuscript.

Corresponding authors

Correspondence to Huilin Ye, Yanan Lu or Quanbo Zhou.

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The authors declare no competing interests.

Ethics approval and consent to participate

The study was conducted in accordance with the principles of the Declaration of Helsinki principles. This study was approved by the Institutional Animal Care and Use Committees of Sun Yat-sen University(SYSU-IACUC-2020-B0229) and Ethics Committee of Sun Yat-sen Memorial Hospital (SYSEC-KY-KS-2021-172).

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Zhang, B., Guo, X., Huang, L. et al. Tumour-associated macrophages and Schwann cells promote perineural invasion via paracrine loop in pancreatic ductal adenocarcinoma. Br J Cancer 130, 542–554 (2024). https://doi.org/10.1038/s41416-023-02539-w

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