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Cellular and Molecular Biology

Apolipoprotein D is crucial for promoting perineural invasion in salivary adenoid cystic carcinoma

British Journal of Cancer volume 132, pages 599–610 (2025)Cite this article

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Abstract

Background

Perineural invasion (PNI) is a prevalent phenomenon in salivary adenoid cystic carcinoma (SACC). Nevertheless, the regulatory mechanism of PNI is largely elusive.

Methods

We detected Apolipoprotein D (ApoD) expression and further determined its role in SACC progression. Subsequently, the contributions of SACC-derived ApoD on neurite outgrowth of dorsal root ganglions (DRGs) cells were explored. Moreover, a series of in vivo assays were conducted to elucidate the role of ApoD in the SACC PNI process.

Results

We observed a dramatic up-regulation of ApoD in the SACC associated with an enhancement of PNI in patient biopsies. We found that SACC-derived ApoD elevated cancer cell migration and invasion. In addition, ApoD could facilitate the neurite outgrowth of cultured DRG cells in a CXCR4-dependent manner in vitro, as well as innervation, angiogenesis, and invasion along peripheral nerves of SACC in vivo. More importantly, by advanced bioinformatic analysis, we unexpectedly revealed a novel phenomenon ‘tumour cell to neuron-like cell transition’ in the ApoD-rich microenvironment in vivo, contributing to the neurogenesis in the SACC tumour.

Conclusion

we discovered a novel role of cancer-derived ApoD in the pathogenesis of PNI, which may represent an effective therapeutic target for SACC in clinics.

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Fig. 1: ApoD was elevated in SACC, and promoted SACC migration and invasion.
Fig. 2: ApoD targeted CXCR4 to accelerate invasion of SACC along nerves.
Fig. 3: ApoD promoted invasion, tumour innervation and angiogenesis in vivo during SACC growth.
Fig. 4: ApoD accelerated SACC cells invasion of peripheral nerves in vivo, and might induce tumour cell to neuron-like cell transition.
Fig. 5: ApoD expression was mediated by JAK2/STAT3 signalling.

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Data availability

The RNA-seq data have been submitted to the GEO database with the accession number is GSE281812.

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Acknowledgements

We sincerely acknowledge Xiaoting Chen and Xijing Yang from the Animal Experimental Center of West China Hospital for technical assistance in animal experiments. In addition, we acknowledge Juan Wu for the data processing and contribution on RNA-Seq submitting.

Funding

This study was funded by the National Natural Science Foundation of China (82270994), the Science and Technology Department of Sichuan Province (2023NSFSC0704, 2023NSFSC0573).

Author information

Author notes

  1. These authors contributed equally: Guangzhao Huang, Su Chen, Bo Han.

Authors and Affiliations

  1. State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Frontier Innovation Center for Dental Medicine Plus & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China

    Guangzhao Huang, Su Chen, Bo Han, Mingzhe Bao, Grace Paka Lubamba, Yufei Hua, Honglin Li & Chunjie Li

  2. Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China

    Gaowei Zhang

  3. Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, 100081, Beijing, China

    Wenwen Liu

  4. State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Frontier Innovation Center for Dental Medicine Plus & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China

    Jiefei Shen

  5. Department of Dentistry, The Second People’s Hospital of Tibet Autonomous Region, Xizang, 850030, China

    Lei Wang

  6. State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Frontier Innovation Center for Dental Medicine Plus & Department of Anesthesiology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China

    Jie Lin

  7. Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, 999077, China

    Patrick Ming-Kuen Tang

  8. State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China

    Zhangfan Ding

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  1. Guangzhao Huang
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Contributions

Huang GZ: methodology, investigation, data curation, visualisation, writing—original draft and writing—review & editing; Chen S: investigation, data curation, formal analysis and visualisation; Han B: investigation, funding acquisition; Zhang GW: investigation; Bao MZ: data curation; Paka Lubamba G: formal analysis; Hua YF: data curation; Li HL: investigation; Liu WW: writing—review & editing; Shen JF: writing—review & editing; Wang L: writing—review & editing; Lin J: supervision, funding acquisition; Patrick Ming-Kuen Tang: supervision and writing—review & editing; Ding ZF: methodology, supervision and writing—review & editing; Li CJ: conceptualisation, methodology, project administration, supervision, funding acquisition and writing—review & editing.

Corresponding authors

Correspondence to Zhangfan Ding or Chunjie Li.

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The authors declare no competing interests.

Ethical approval

Written informed consent was obtained from all patients. This study was approved by the Ethical Committee of West China School of Stomatology, Sichuan University (WCHSIRB-D-2022-445). All animal experiments were approved by the Animal Ethical Committee of West China School of Stomatology, Sichuan University (WCHSIRB-D-2022-337). All methods were performed in accordance with the relevant guidelines and regulations.

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Huang, G., Chen, S., Han, B. et al. Apolipoprotein D is crucial for promoting perineural invasion in salivary adenoid cystic carcinoma. Br J Cancer 132, 599–610 (2025). https://doi.org/10.1038/s41416-025-02946-1

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