Identification of a minority population of LMO2⁺ breast cancer cells that integrate into the vasculature and initiate metastasis.

Abstract

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 immature <i>THY1</i>⁺/<i>VEGFA</i>⁺ tumor epithelial cells in human breast tumor biopsies that display angiogenic features and are marked by the expression of the oncogene, <i>LMO2</i>. Higher abundance of <i>LMO2</i>⁺ basal cells correlated with tumor endothelial content and predicted poor distant recurrence-free survival in patients. Using <i>MMTV-PyMT/Lmo2^CreERT2</i> mice, we demonstrated that <i>Lmo2</i> lineage-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.