1. Modulating bone marrow hematopoietic lineage potential to prevent bone metastasis in breast cancer
- Author
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Ubellacker, J.M., Baryawno, N., Severe, N., DeCristo, M.J., Sceneay, J., Hutchinson, J.N., Haider, M.-T., Rhee, C.S., Qin, Y., Gregory, W.M., Garrido-Castro, A.C., Holen, I., Brown, J.E., Coleman, R.E., Scadden, D.T., and McAllister, S.S.
- Abstract
The presence of disseminated tumor cells in breast cancer patient bone marrow aspirates predicts decreased recurrence-free survival. Although it is appreciated that physiological, pathological, and therapeutic conditions impact hematopoiesis, it remains unclear if targeting hematopoiesis presents opportunities for limiting bone metastasis. Using pre-clinical breast cancer models, we discovered that marrow from mice treated with the bisphosphonate zoledronic acid (ZA) are metastasis-suppressive. Specifically, ZA modulated hematopoietic myeloid/osteoclast progenitor cell (M/OCP) lineage potential to activate metastasis-suppressive activity. Granulocyte-colony stimulating factor (G-CSF) promoted ZA resistance by redirecting M/OCP differentiation. We identified M/OCP and bone marrow transcriptional programs associated with metastasis suppression and ZA resistance. Analysis of patient blood samples taken at random revealed that women with high plasma G-CSF experienced significantly worse outcome with adjuvant ZA than those with lower G-CSF levels. Our findings support discovery of therapeutic strategies to direct M/OCP lineage potential and biomarkers that stratify responses in patients at risk of recurrence.
- Published
- 2018