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

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

doi:10.1038/s41388-025-03462-5

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

Oncogene. 2025 Jun 5. doi: 10.1038/s41388-025-03462-5. Online ahead of print.

Authors

Wuhu Zhang^#^{1

2

3

4

5

6}, Junfeng Xu^#^{1

2

3

4

5

6}, Dan Huang^#^{3

7}, Yi Qin^#^{1

2

3

4

5

6}, Xin Lou^#^{1

2

3

4

5

6}, Heli Gao^{1

2

3

4

5

6}, Zeng Ye^{1

2

3

4

5

6}, Fei Wang^{1

2

3

4

5

6}, Yan Wang^{1

2

3

4

5

6}, Desheng Jing^{1

2

3

4

5

6}, Guixiong Fan^{1

2

3

4

5

6}, Qifeng Zhuo^{1

2

3

4

5

6}, Chang Xin⁸, Jie Chen^{9

10}, Xiaowu Xu^{11

12

13

14

15

16}, Xianjun Yu^{17

18

19

20

21

22}, Shunrong Ji^{23

24

25

26

27

28}

Affiliations

¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
² Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China.
³ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
⁴ Shanghai Pancreatic Cancer Institute, Shanghai, China.
⁵ Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China.
⁶ Pancreatic Cancer Institute, Fudan University, Shanghai, China.
⁷ Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
⁸ The Affiliated People' s Hospital of NingBo University, Ningbo, Zhejiang Province, China.
⁹ Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China. chen0jie@hotmail.com.
¹⁰ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. chen0jie@hotmail.com.
¹¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. xuxiaowu@fudanpci.org.
¹² Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China. xuxiaowu@fudanpci.org.
¹³ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. xuxiaowu@fudanpci.org.
¹⁴ Shanghai Pancreatic Cancer Institute, Shanghai, China. xuxiaowu@fudanpci.org.
¹⁵ Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China. xuxiaowu@fudanpci.org.
¹⁶ Pancreatic Cancer Institute, Fudan University, Shanghai, China. xuxiaowu@fudanpci.org.
¹⁷ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. yuxianjun@fudanpci.org.
¹⁸ Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China. yuxianjun@fudanpci.org.
¹⁹ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. yuxianjun@fudanpci.org.
²⁰ Shanghai Pancreatic Cancer Institute, Shanghai, China. yuxianjun@fudanpci.org.
²¹ Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China. yuxianjun@fudanpci.org.
²² Pancreatic Cancer Institute, Fudan University, Shanghai, China. yuxianjun@fudanpci.org.
²³ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. jishunrong@fudanpci.org.
²⁴ Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China. jishunrong@fudanpci.org.
²⁵ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. jishunrong@fudanpci.org.
²⁶ Shanghai Pancreatic Cancer Institute, Shanghai, China. jishunrong@fudanpci.org.
²⁷ Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China. jishunrong@fudanpci.org.
²⁸ Pancreatic Cancer Institute, Fudan University, Shanghai, China. jishunrong@fudanpci.org.

^# Contributed equally.

PMID: 40473904
DOI: 10.1038/s41388-025-03462-5

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.

Abstract

Grants and funding