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Cellular and Molecular Biology

SPP1 represents a therapeutic target that promotes the progression of oesophageal squamous cell carcinoma by driving M2 macrophage infiltration

British Journal of Cancer (2024)Cite this article

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Abstract

Background

Tumour-associated macrophages (TAMs) are an important component of the tumour microenvironment (TME). However, the crosstalk between oesophageal squamous cell carcinoma (ESCC) cells and TAMs remains largely unexplored.

Methods

Clinical samples and the TCGA database were used to evaluate the relevance of SPP1 and TAM infiltration in ESCC. Mouse models were constructed to investigate the roles of macrophages educated by SPP1 in ESCC. Macrophage phenotypes were determined using qRT‒PCR and immunohistochemical staining. RNA sequencing was performed to elucidate the mechanism.

Results

Increasing expression of SPP1 correlated with M2-like TAM accumulation in ESCC, and they both predicted poor prognosis in the ESCC cohort. Knockdown of SPP1 significantly inhibited the infiltration of M2 TAMs in xenograft tumours. In vivo mouse model experiments showed that SPP1-mediated education of macrophages plays an essential role in the progression of ESCC. Mechanistically, SPP1 recruited macrophages and promoted M2 polarisation via CD44/PI3K/AKT signalling activation and then induced VEGFA and IL6 secretion to sustain ESCC progression. Finally, blockade of SPP1 with RNA aptamer significantly inhibited tumour growth and M2 TAM infiltration in xenograft mouse models.

Conclusions

This study highlights SPP1-mediated crosstalk between ESCC cells and TAMs in ESCC. SPP1 could serve as a potential target in ESCC therapy.

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Fig. 1: SPP1 is highly expressed in EC patients and correlates with poor survival.
Fig. 2: SPP1 expression positively correlates with M2 macrophage infiltration in ESCC patients.
Fig. 3: SPP1 promotes tumour growth and the infiltration of M2 TAMs in ESCC in xenograft models.
Fig. 4: SPP1 plays a key role in ESCC cells for recruitment and polarisation of macrophages.
Fig. 5: Macrophages play a prominent role in the SPP1-mediated promotion of ESCC.
Fig. 6: SPP1 activates CD44/PI3K/AKT signalling to promote M2 polarisation of macrophages in ESCC.
Fig. 7: The SPP1 aptamer suppresses tumour growth and M2 macrophage polarisation in ESCC.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

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Acknowledgements

We thank Prof. Jianying Zhang for suggestions on the study design and revision of the paper.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82203287 to Renle Du), the China Postdoctoral Science Foundation (No. 2022M722874 to Renle Du), the Key Scientific and Technological Project of Henan Province (No. 242102311154 to Renle Du), and the Project of Basic Research Fund of Henan Institute of Medical and Pharmacological Sciences (No. 2023BP0204 to Renle Du).

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Authors and Affiliations

  1. Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China

    Chen Wang, Yutong Li, Linhong Wang, Xiaohui Gao, Liping Dai & Renle Du

  2. Department of Nuclear Medicine, Xinxiang Central Hospital, Xinxiang, 453002, Henan, China

    Chen Wang

  3. Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou University, Zhengzhou, 450052, Henan, China

    Yutong Li, Linhong Wang, Xiaohui Gao, Liping Dai & Renle Du

  4. Henan Key Laboratory for Pharmacology of Liver Diseases, Zhengzhou University, Zhengzhou, 450052, Henan, China

    Yutong Li, Linhong Wang, Xiaohui Gao, Liping Dai & Renle Du

  5. Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China

    Yu Han

  6. College of Public Health, Zhengzhou University, Zhengzhou, 450052, Henan, China

    Tiandong Li & Renle Du

  7. Laboratory of Molecular Biology, Henan Luoyang Orthopedic Hospital (Henan Provincial Orthopedic Hospital), Zhengzhou, 450000, Henan, China

    Man Liu

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Contributions

CW performed the experiments and drafted the manuscript. YTL, LHW and XHG provided the materials for experiments and data analysis. YH, TDL, ML and LPD revised the manuscript. RLD designed and edited the manuscript. The authors read and approved the final manuscript.

Corresponding author

Correspondence to Renle Du.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participants

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Zhengzhou University. The animal experiments of this study were approved by the Institutional Animal Care and Use Committee of the Zhengzhou University (Ethic approved number: 2019003). The maximal tumour size/burden permitted by the ethics committee is 2 cm3; we confirmed that during this study the maximal tumour size/burden was not exceeded. The animal experiments were conducted in accordance with the ARRIVE guidelines.

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Wang, C., Li, Y., Wang, L. et al. SPP1 represents a therapeutic target that promotes the progression of oesophageal squamous cell carcinoma by driving M2 macrophage infiltration. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02683-x

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