Cancer EVP Uptake in Lung Interstitial Macrophages Enhances Vascular Permeability and Metastatic Potential (in vitro)

Enhanced vascular permeability in the pre-metastatic niche facilitates tumor cell extravasation and metastasis. Extracellular vesicles and particles (EVPs) are pivotal mediators of cancer progression, including induction of vascular permeability. We identify a novel mechanism whereby melanoma and osteosarcoma EVPs (B16F10 and K7M2) enhance endothelial cell permeability, tumor extravasation and lung metastasis.In contrast, EVPs from breast tumors (4T1 and 67NR) elicited only mild vascular permeability, tumor cell extravasation, and metastasis. EVP induced vascular leakiness is observed within 48h following tumor implantation and as early one hour following direct injection of the B16F10 or K7M2 derived EVPs in non-tumor bearing mice. Rather than acting directly on endothelial cells, EVPs activated interstitial macrophages (IMs) anddepletion of IM with a CSF1R antibody significantly reduced vascular leakiness and metastatic potential.Subsequent activation of JAK/STAT signaling in IMs induces IL-6 secretion which in turn induces endothelial permeability.B16F10 and K7M2 EVPs highly expressed integrin-α5 compared to breast tumors, and knock down ofITGα5impairs IM signaling, vascular permeability and metastasis. Furthermore, in patients Il-6 expression is elevated in tumor-adjacent IMs compared to distant tissues. Our findings identify a key role for IMs in mediating tumor type-specific EVP-driven vascular permeability and metastasis, offering promising targets for therapeutic intervention.