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Background <p>Metastatic recurrence represents the major clinical challenge in early-stage lung cancer after curative surgery. Here, we investigated the role of circulating extracellular vesicles and particles (EVPs) in promoting formation of pre-metastatic niches (PMNs).</p> Methods <p>Plasma-derived EVPs were obtained by ultracentrifugation from pre-surgery blood samples of patients with poor prognosis. Heavy-smokers cancer free individuals were used as control. EVP were characterized following MISEV guidelines. Functional experiments were carried out in vitro in 2D and 3D-bioprinted models as well as in vivo<i>.</i></p> Results <p>EVPs from patients with early relapse show distinct molecular profiles, characterized by elevated levels of miR-29a and complement protein C4a. These EVPs preferentially target endothelial cells inducing a pro-inflammatory condition with upregulation of VCAM1 and CXCL1. In turn, endothelial modulation stimulated fibroblast activation and promoted neutrophils recruitment supporting PMNs formation. Mechanistically, we demonstrate that miR-29a and C4A act synergistically through SPARC down-modulation promoting cancer cell colonization. Preconditioning of mouse lungs using EVPs from patients with poor prognosis increased metastatic growth of human tumor cells, which was inhibited by miR-29a blockade.</p> Conclusions <p>Circulating EVPs could be novel prognostic biomarkers and key players in PMN formation offering new targets to reduce relapses in lung cancer.</p> Graphical Abstract <p></p>

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Circulating extracellular vesicles from early-stage lung cancer patients trigger endothelial activation to drive pre-metastatic niche formation through synergistic miR-29a and C4A signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Francesca Pontis,
  • Patrizia Ghidotti,
  • Nicole Ferrario,
  • Camilla Locatelli,
  • Mattia Boeri,
  • Marco Gentili,
  • Miriam Segale,
  • Massimo Moro,
  • Arianna Di Bernardo,
  • Giulia Bertolini,
  • Paola Suatoni,
  • Michele Ferrari,
  • Ugo Pastorino,
  • Loris De Cecco,
  • Marica Ficorilli,
  • Marta Lucchetta,
  • Silvia Brich,
  • Luca Agnelli,
  • Fabio Maiullari,
  • Roberto Rizzi,
  • Claudia Bearzi,
  • Paola Portararo,
  • Sabina Sangaletti,
  • Rossella Crescitelli,
  • Luca Roz,
  • Gabriella Sozzi,
  • Orazio Fortunato

摘要

Background

Metastatic recurrence represents the major clinical challenge in early-stage lung cancer after curative surgery. Here, we investigated the role of circulating extracellular vesicles and particles (EVPs) in promoting formation of pre-metastatic niches (PMNs).

Methods

Plasma-derived EVPs were obtained by ultracentrifugation from pre-surgery blood samples of patients with poor prognosis. Heavy-smokers cancer free individuals were used as control. EVP were characterized following MISEV guidelines. Functional experiments were carried out in vitro in 2D and 3D-bioprinted models as well as in vivo.

Results

EVPs from patients with early relapse show distinct molecular profiles, characterized by elevated levels of miR-29a and complement protein C4a. These EVPs preferentially target endothelial cells inducing a pro-inflammatory condition with upregulation of VCAM1 and CXCL1. In turn, endothelial modulation stimulated fibroblast activation and promoted neutrophils recruitment supporting PMNs formation. Mechanistically, we demonstrate that miR-29a and C4A act synergistically through SPARC down-modulation promoting cancer cell colonization. Preconditioning of mouse lungs using EVPs from patients with poor prognosis increased metastatic growth of human tumor cells, which was inhibited by miR-29a blockade.

Conclusions

Circulating EVPs could be novel prognostic biomarkers and key players in PMN formation offering new targets to reduce relapses in lung cancer.

Graphical Abstract