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

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 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 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.

Methods
Brief overview

Please find enclosed in this repository two main folders:

(1) 'data', which contains raw and processed data used for the genomic analysis done in the manuscript including original scRNA-seq data from our laboratory and publicly available scRNA-seq data from other labs, and

(2) 'scripts', which contains the code and scripts used to generate the results shown in the figures. Please reach out directly to us if you have any questions about the data and scripts enclosed here for the manuscript.