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

Pulmonary lymphangioleiomyomatosis (LAM) is a metastatic sarcoma, but the mechanisms of LAM metastasis are unknown. Extracellular vesicles (EVs) regulate cancer metastasis; however, 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 the shuttling of 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 lung metastatic burden upon exposure to EVs 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 biogenesis in LAM patients and the enrichment of these EV cargo with lung-tropic integrins and metalloproteinases. These findings establish EVs as a novel therapeutic target in LAM, warranting future clinical studies.