Blood particles from lung cancer patients reveal how tumors spread
Researchers identified molecular signals in tiny particles circulating in blood that prepare distant organs to receive cancer cells—a process called pre-metastatic niche formation. The discovery could enable earlier detection of patients at high relapse risk after surgery and potentially lead to therapies that block metastasis before it starts.
Originaltitel: 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
Abstract 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