Dissecting tumor-stromal interactions in breast cancer bone metastasis

Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complicationssuch as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communicationsbetween tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signalingpathways, secreted micro RNAs (miRNAs) and exosomes are functional mediators of tumor-stromal interactions in bone metastasis.We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancercells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascularcell adhesion molecule 1 (VCAM1) in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotestheir differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β) is releasedfrom bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis.We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activationof Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantiallychange in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploitedas circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Furtherresearch in this direction may lead to improved diagnosis and treatment strategies for bone metastasis.