Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma

Xiang H.F. Zhang, Xin Jin, Srinivas Malladi, Yilong Zou, Yong H. Wen, Edi Brogi, Marcel Smid, John A. Foekens, Joan Massagué

Research output: Contribution to journalArticle

207 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1060-1073
Number of pages14
JournalCell
Volume154
Issue number5
DOIs
StatePublished - Aug 29 2013

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhang, X. H. F., Jin, X., Malladi, S., Zou, Y., Wen, Y. H., Brogi, E., Smid, M., Foekens, J. A., & Massagué, J. (2013). Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell, 154(5), 1060-1073. https://doi.org/10.1016/j.cell.2013.07.036