Extracellular vesicles modulate integrin signaling and subcellular energetics to promote pulmonary lymphangioleiomyomatosis metastasis.

Pulmonary lymphangioleiomyomatosis (LAM) is metastatic sarcoma but mechanisms of LAM metastasis are unknown. Extracellular vesicles (EV) regulate cancer metastasis but their roles in LAM have not yet been thoroughly investigated. Here, we report the discovery of distinct LAM-EV subtypes derived from primary tumor or metastasizing LAM cells that promote LAM metastasis through ITGα6/β1-c-Src-FAK signaling, triggered by shuttling ATP synthesis to cell pseudopodia or the activation of integrin adhesion complex, respectively. This signaling leads to increased LAM cell migration, invasiveness, and stemness and regulates metastable (hybrid) phenotypes that are all pivotal for metastasis. Mouse models corroborate in vitro data by demonstrating a significant increase in metastatic burden upon the exposure to EV through distinct mechanisms involving either lung resident fibroblasts or metalloproteinases' activation that are EV subtype dependent. The clinical relevance of these findings is underscored by increased EV biogenies in LAM patients and the enrichment of these EV cargo with lung tropic integrins and metalloproteinases. These findings establish EV as novel therapeutic target in LAM, warranting the future clinical studies.