Breast cancer stem cell-derived exosomal lnc-PDGFD induces fibroblast-niche formation and promotes lung metastasis

Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastatic potential and lack of therapeutic targets. Breast cancer stem cells (BCSCs) are enriched in TNBC and contribute to its metastatic propensity. Accumulating evidence suggests that cancer-derived exosomes are key drivers of premetastatic niche formation in distal organs. However, the function and underlying mechanism of BCSC-derived exosomes in TNBC metastasis remain elusive. Here, we demonstrated that BCSC-derived exosomes exhibit a greater capacity to activate fibroblasts and promote TNBC cell metastasis to the lung than non-BCSC-derived exosomes. Additionally, we found that upregulation of exosomal long non-coding RNA platelet derived growth factor D (lnc-PDGFD) expression in BCSCs is responsible for fibroblast activation through YBX1/NF-kB signaling in the lung. Activated fibroblasts further promote tumor progression by secreting IL-11. Taken together, BCSC-derived exosomes enriched with lnc-PDGFD could activate fibroblasts, thereby facilitating lung metastasis in TNBC patients. These results provide new insights into the mechanism of TNBC metastasis to the lung.