How organ-specific metastatic traits arise in primary tumors remains unknown. Here, we show a role of the breast tumor stroma in selecting cancer cells that are primed for metastasis in bone. Cancer-associated fibroblasts (CAFs) in triple-negative (TN) breast tumors skew heterogeneous cancer cell populations toward a predominance of clones that thrive on the CAF-derived factors CXCL12 and IGF1. Limiting concentrations of these factors select for cancer cells with high Src activity, a known clinical predictor of bone relapse and an enhancer of PI3K-Akt pathway activation by CXCL12 and IGF1. Carcinoma clones selected in this manner are primed for metastasis in the CXCL12-rich microenvironment of the bone marrow. The evidence suggests that stromal signals resembling those of a distant organ select for cancer cells that are primed for metastasis in that organ, thus illuminating the evolution of metastatic traits in a primary tumor and its distant metastases.

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doi.org/10.1016/j.cell.2013.07.036, hdl.handle.net/1765/41497
Cell
Erasmus MC: University Medical Center Rotterdam

Zhang, X., Jin, X., Malladi, S., Zou, Y., Wen, Y., Brogi, E., … Massagué, J. (2013). Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell, 154(5), 1060–1073. doi:10.1016/j.cell.2013.07.036