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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年6月5日

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  • 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

摘要

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.