| Metastasis is the leading cause of deaths from cancer. Yet little is known how metastatic traits arise in primary tumors. Querying bone metastatic origin in breast tumors, we identified a role of the breast tumor stroma in driving bone metastasis tropism. Cancer-associated fibroblasts (CAFs) in triple-negative breast tumors skew heterogeneous cancer cell populations towards a predominance of clones that thrive on the CAF-derived factors CXCL12 and IGF1. These cytokines select for cancer clones with high Src activity, a clinical predictor of bone relapse and an enhancer of PI3K-AKT pathway activation by CXCL12 and IGF1. High Src activity confers these metastasis seeds a survival advantage when they disseminate and lodge in the bone marrow, an organ site that is also rich in CXCL12 and IGF1. Thus stromal signals resembling those of a distant organ in primary tumors select for cancer cells that are primed for metastasis in that organ. The dependency of metastasis seeds on Sic and its amplified signaling PI3K-AKT pathway indicates these genes as targets for clinical intervention. Pharmacological inhibitors of P13K, AKT or Src inhibited the initial survival of metastasis seeds and their bone metastasis formation. These results provide a proof-of-principle for metastasis prevention and reveal tremendous potentials of targeted therapy against metastases, when cellular dependency is clear. |
