Extracellular Vesicle–Packaged CDH11 and ITGA5 Induce the Premetastatic Niche for Bone Colonization of Breast Cancer Cells

Although most breast cancer metastases in bone cause osteolytic lesions, the osteogenic niche has commonly been described as an initiator of early-stage bone colonization of disseminated cancer cells. Tumor cell-derived extracellular vesicles (EV) have been shown to determine the organotropism of cancer cells by transferring their cargo, such as nucleic acids and proteins, to resident cells at future metastatic sites and preparing a favorable premetastatic niche. Runt-related transcription factor 2 (RUNX2) and its regulated genes have been shown to facilitate the acquisition of osteomimetic features and to enhance the bone metastatic potential of breast cancer cells. In this study, we present in vivo and in vitro evidence to clarify the role of EVs released by breast cancer cells with high RUNX2 expression in the education of osteoblasts to form an osteogenic premetastatic niche. Furthermore, different extracellular vesicular proteins were identified that mediate events subsequent to the specific recognition of tumor-derived EVs by osteoblasts via cadherin 11 (CDH11) and the induction of the osteogenic premetastatic niche by integrin α5 (ITGA5). CDH11high/ITGA5high EVs were demonstrated to be responsible for the formation of a premetastatic niche that facilitates RUNX2 high-expressing breast cancer cell colonization in bone, revealing a potential EV-based premetastatic niche blockage strategy. SIGNIFICANCE: This study provides mechanistic insights into the generation of an osteogenic premetastatic niche by breast cancer-derived EVs and identifies potential EV-derived diagnostic biomarkers and targets for breast cancer bone metastasis.