Exosomes from Cancer-associated Fibroblasts Orchestrate Lung Metastasis of Breast Cancer via LncRNA LMAEP.

Abstract

Lung metastasis is a leading cause of patient mortality in breast cancer. Cancer-associated fibroblasts (CAFs), the most abundant stromal cells within the tumor microenvironment, are closely implicated in pulmonary metastasis. Nevertheless, the mechanism underlying CAF-mediated metastasis remains elusive. We found that density of CAFs in primary tumors showed no significant difference in patients with or without lung metastasis. However, CAFs of breast cancer patients with lung metastasis (termed lung metastasis-associated fibroblasts, LMAFs) exhibited immense competence in inducing epithelial-mesenchymal transition (EMT), invasion and proliferation of tumor cells relative to non-metastatic CAFs. LMAF-derived exosomes were sufficient to confer the pro-metastatic phenotype to tumor cells. LncRNA microarray screening identified LMAEP (Lung Metastasis-Associated EMT Promoter) as a lncRNA specifically enriched in LMAF-derived exosomes. Knockdown of LMAEP abrogated the capacity of LMAFs to induce cancer cell EMT, invasion and proliferation. Targeting of lncRNA LMAEP tremendously suppressed tumor growth and lung metastasis of breast cancer in vivo. These findings identify LMAEP as a critical metastasis-inducing mediator of CAFs, positioning it as a potential biomarker for risk prediction and early detection of lung metastasis. Furthermore, targeting exosomal lncRNA LMAEP represents a promising therapeutic strategy for restraining pulmonary metastasis of breast cancer.