Modulating Bone Marrow Hematopoietic Lineage Potential to Prevent Breast Cancer Bone Metastasis

The presence of disseminated tumor cells in patient bone marrow (BM) aspirates predicts decreased recurrence-free survival, yet little is known about whether hematopoietic BM cells impact bone metastases. Here, we report that the BM can be rendered metastasis-suppressive by the bone-targeting bisphosphonate, zoledronic acid (ZA). In particular, ZA modulates hematopoietic myeloid/osteoclast progenitor cell (M/OCP) lineage potential to render them metastasis-suppressive. Granulocyte-colony stimulating factor (G-CSF) promotes resistance to ZA by re-directing M/OCP differentiation. We identified BM transcriptional programs that associate with metastasis suppression and resistance to ZA. Analysis of patient blood samples taken at randomization revealed that women with plasma G-CSF levels >23 pg/mL experienced significantly worse outcome with adjuvant ZA than those on ZA who had lower plasma G-CSF levels. Our findings establish that hematopoietic cells and M/OCP lineage potential profoundly impact bone metastasis and support the discovery of biomarkers that stratify therapeutic responses in patients at risk of recurrence. Overall design: To test in murine bone marrow and osteoclast precursor cells the effects on gene expression of treatment with ZA and G-CSF. At least two replicates from each treatment were used (including no treatment and combination treatment) and analyzed in a pairwise fashion.