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Small extracellular vesicle-miR-183-5p mediated crosstalk between tumor cells and macrophages in high-risk pancreatic neuroendocrine tumors

Oncogene volume 44, pages 2907–2923 (2025)Cite this article

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Abstract

High-risk pancreatic neuroendocrine tumors (pNET) are characterized by aggressive progression and metastasis, contributing to poor clinical outcomes. This study explores molecular mechanisms underlying metastasis in high-risk pNETs and evaluates therapeutic interventions. We employed small RNA sequencing to profile miRNA signatures in tumor-derived small extracellular vesicles (sEVs) and integrated single-cell transcriptomic analysis to delineate the tumor immune microenvironment. Prognostic validation of SPP1+ macrophages was performed in clinical cohorts using multiplex immunofluorescence. Mechanistic studies utilized animal models and functional assays to elucidate the sEV-mediated crosstalk between tumor cells and macrophages. Here, we reveal that sEV-miR-183-5p from high-risk pNETs reprograms macrophages via PDCD4/PI3Kγ/AKT/mTOR signaling, inducing SPP1 overexpression and M2 polarization to promote angiogenesis and metastasis. p53 mutants were identified as upstream regulators of sEV-miR-183-5p secretion. Inhibition of SPP1 attenuated tumor progression, while elevated plasma sEV-miR-183-5p levels correlated with high-grade and advanced disease stages. Together, this study reveals a critical sEV-miRNA mediated mechanism governing tumor-macrophage communication in high-risk pNETs, offering insights into therapeutic strategies and suggesting sEV-miR-183-5p may have prognostic potential.

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Fig. 1: Comprehensive analysis of miRNA profiles in pNET-derived sEVs and single-cell sequencing of high-/low-risk pNET samples.
Fig. 2: SPP1+ macrophage infiltration in high-risk pNETs.
Fig. 3: High-risk sEVs induce macrophage-mediated tumor progression.
Fig. 4: miR-183-5p enrichment in high-risk pNET-derived sEVs.
Fig. 5: miR-183-5p-enriched sEV-treated macrophages promote tumor progression via PDCD4/PI3Kγ/AKT/mTOR axis.
Fig. 6: The accumulation of p53 mutants drives sEV-miR-183-5p secretion.
Fig. 7: miR-183-5p-rich sEVs treated macrophages promoted tumor progression, metastasis, and angiogenesis in vivo.
Fig. 8: Higher sEV-miR-183-5p correlated with higher recurrence.

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Data availability

Raw data for the scRNA-seq has been deposited in Gene Expression Omnibus (GEO) (GSE256136), which are publicly available. The raw data generated by small RNA sequencing of sEVs, ATAC-seq, and RNA sequencing are deposited in Genome Sequence Archive (GSA) database (https://ngdc.cncb.ac.cn/gsa/) and can be access by searching for bioproject PRJCA024087. The raw data generated by whole exome sequencing can be access by searching for bioproject PRJCA026652. Access to the raw data may be requested by completing the application form via GSA-Human System and is granted by the corresponding Data Access Committee. The approximate response time for accession requests is about 10 working days. Additional guidance can be found at the GSA-Human website [https://ngdc.cncb.ac.cn/gsa-human/document/GSAHuman_Request_Guide_for_Users_us.pdf]. This study did not generate original codes. All software and algorithms used in this study are publicly available.

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Funding

This research was funded by the National Natural Science Foundation of China (82473108, 82472791, 82473108, 82141129, 82141104, and 82303943). Shanghai Pujiang Program (22PJ1401800). Sailing Project of Science and Technology Commission of Shanghai Municipality (23YF1406900), China Postdoctoral Science Foundation (2023M730670). National Natural Science Foundation of China (U21A20374), Shanghai Municipal Science and Technology Major Project (21JC1401500), Shanghai Municipal Health Commission’s Collaborative Guidance Project for Traditional Chinese and Western Medicine (ZXXT-202201), Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057), Clinical Research Plan of Shanghai Hospital Development Center (SHDC2020CR1006A), and Xuhui District Artificial Intelligence Medical Hospital Cooperation Project (2021-011).

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Author notes

  1. These authors contributed equally: Wuhu Zhang, Junfeng Xu, Dan Huang, Yi Qin, Xin Lou.

Authors and Affiliations

  1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

    Wuhu Zhang, Junfeng Xu, Yi Qin, Xin Lou, Heli Gao, Zeng Ye, Fei Wang, Yan Wang, Desheng Jing, Guixiong Fan, Qifeng Zhuo, Xiaowu Xu, Xianjun Yu & Shunrong Ji

  2. Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China

    Wuhu Zhang, Junfeng Xu, Yi Qin, Xin Lou, Heli Gao, Zeng Ye, Fei Wang, Yan Wang, Desheng Jing, Guixiong Fan, Qifeng Zhuo, Jie Chen, Xiaowu Xu, Xianjun Yu & Shunrong Ji

  3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Wuhu Zhang, Junfeng Xu, Dan Huang, Yi Qin, Xin Lou, Heli Gao, Zeng Ye, Fei Wang, Yan Wang, Desheng Jing, Guixiong Fan, Qifeng Zhuo, Jie Chen, Xiaowu Xu, Xianjun Yu & Shunrong Ji

  4. Shanghai Pancreatic Cancer Institute, Shanghai, China

    Wuhu Zhang, Junfeng Xu, Yi Qin, Xin Lou, Heli Gao, Zeng Ye, Fei Wang, Yan Wang, Desheng Jing, Guixiong Fan, Qifeng Zhuo, Xiaowu Xu, Xianjun Yu & Shunrong Ji

  5. Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China

    Wuhu Zhang, Junfeng Xu, Yi Qin, Xin Lou, Heli Gao, Zeng Ye, Fei Wang, Yan Wang, Desheng Jing, Guixiong Fan, Qifeng Zhuo, Xiaowu Xu, Xianjun Yu & Shunrong Ji

  6. Pancreatic Cancer Institute, Fudan University, Shanghai, China

    Wuhu Zhang, Junfeng Xu, Yi Qin, Xin Lou, Heli Gao, Zeng Ye, Fei Wang, Yan Wang, Desheng Jing, Guixiong Fan, Qifeng Zhuo, Xiaowu Xu, Xianjun Yu & Shunrong Ji

  7. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China

    Dan Huang

  8. The Affiliated People’ s Hospital of NingBo University, Ningbo, Zhejiang Province, China

    Chang Xin

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  1. Wuhu Zhang
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Contributions

Conceptualization, WZ, JX, XX, XY, and SJ; methodology, WZ, JX, DH, YQ, XL, ZY, FW, YW, DJ, GF, QZ, and CX; analysis, WZ, JX, DH, YQ, XL, and HG; writing—original draft preparation, all authors; writing—review and editing, all authors; supervision, YQ, JC, XX, XY, and SJ; project administration, WZ, DH, HG, ZY, FW, YW, DJ, GF, QZ, CX, JC, XY, and SJ; funding acquisition, JX, YQ, ZY, JC, XX, XY, and SJ. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Jie Chen, Xiaowu Xu, Xianjun Yu or Shunrong Ji.

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Zhang, W., Xu, J., Huang, D. et al. Small extracellular vesicle-miR-183-5p mediated crosstalk between tumor cells and macrophages in high-risk pancreatic neuroendocrine tumors. Oncogene 44, 2907–2923 (2025). https://doi.org/10.1038/s41388-025-03462-5

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