LMO2 is critical for early metastatic events in breast cancer
Sikandar, S. S.; Antony, J.; Gulati, G. S.; Kuo, A.; Ho, W. H. D.; Das, S.; Steen, C. B.; Pereira, T. A.; Qian, D.; Beachy, P. A.; Dirbas, F.; Red-Horse, K.; Rabbitts, T. H.; Thiery, J. P.; Newman, A. M.; Clarke, M.
Show abstract
Metastasis is responsible for the majority of breast cancer-related deaths, however identifying the cellular determinants of metastasis has remained challenging. Here, we identified a minority population of immature THY1+/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 of LMO2+ basal cells correlated with tumor endothelial content and predicted poor distant recurrence-free survival in patients. Using MMTV-PyMT/Lmo2CreERT2 mice, we demonstrated that Lmo2 lineage- traced cells 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 TNF and IL6. 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. One sentence summaryLMO2 modulates STAT3 signaling in breast cancer metastasis.
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