SUMMARY
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 TNFα 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 summary LMO2 modulates STAT3 signaling in breast cancer metastasis.
Competing Interest Statement
A.M.N. has patent filings related to expression deconvolution and digital cytometry, and has served as a consultant for Roche, Merck and CiberMed. A.M.N., G.S.G., S.S.S., and M.F.C. have patent filings related to differentiation prediction and therapeutic targets for breast cancer.
Footnotes
↵‡ Co-senior authors
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159285