Identification of a minority population in breast cancer that integrates into the vasculature and initiates metastasis [scRNA-Seq]

Metastasis is responsible for the majority of cancer-related deaths1. Although single-cell RNA sequencing (scRNA-seq) has revealed considerable heterogeneity among tumor cells, identifying the cellular determinants of metastasis has remained challenging. Here, we analyzed scRNA-seq data of primary human breast tumor biopsies and identified a minority population of immature THY1+/VEGFA+ basal epithelial cells that display angiogenic features and are marked by the expression of the oncogene, LMO2. Higher levels of LMO2+ basal cells in human breast tumors correlated with endothelial content and predicted poor distant recurrence-free survival. Using MMTV-PyMT/Lmo2CreERT2 mice, we demonstrate that Lmo2 lineage-traced cells integrate into the vasculature and metastasize to the lung. In human breast tumors, knockdown of LMO2 reduced lung metastasis by affecting multiple steps required for intravasation, leading to a reduced frequency of circulating tumor cells. Mechanistically, we find that LMO2 is a binding partner of STAT3 and is required for STAT3 activation in the presence of the inflammatory cytokines, 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. Single-cell RNA-sequencing (Smart-seq2) profiles (n = 2,359 cells) of basal (tumor: n = 518, adjacent normal: n = 392), luminal progenitor (tumor: n = 213, adjacent normal: n = 319), mature luminal cells (tumor: n = 354, adjacent normal: n = 356), cancer-associated fibroblasts (CAFs; n = 6), endothelial cells (ECs; n = 126), macrophages (n = 21), CD4 T cells (n = 22), CD8 T cells (n = 21), and B cells (n = 11) from 18 human breast tumor biopsies. This study includes data from GSE138536. ----------------------------------------- The authors state that they will "upload the remaining raw data to dbGap".