American Association for the Advancement of Science, Science Advances, 45(8), 2022
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Metastasis is responsible for most breast cancer–related deaths; however, identifying the cellular determinants of metastasis has remained challenging. Here, we identified a minority population of immatureTHY1+/VEGFA+tumor epithelial cells in human breast tumor biopsies that display angiogenic features and are marked by the expression of the oncogene,LMO2. Higher abundance ofLMO2+basal cells correlated with tumor endothelial content and predicted poor distant recurrence–free survival in patients. UsingMMTV-PyMT/Lmo2CreERT2mice, we demonstrated thatLmo2lineage–traced cells integrate into the vasculature and have a higher propensity to metastasize. LMO2 knockdown in human breast tumors reduced lung metastasis by impairing intravasation, leading to a reduced frequency of circulating tumor cells. Mechanistically, we find that LMO2 binds to STAT3 and is required for STAT3 activation by tumor necrosis factor–α and interleukin-6. Collectively, our study identifies a population of metastasis-initiating cells with angiogenic features and establishes the LMO2-STAT3 signaling axis as a therapeutic target in breast cancer metastasis.