Identification of a minority population of LMO2+ breast cancer cells that integrate into the vasculature and initiate metastasis
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons biopsiques prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence un mécanisme par lequel une population minoritaire de cellules cancéreuses exprimant fortement la protéine LMO2 favorise le processus métastatique
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 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 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. LMO2 modulates STAT3 signaling to promote breast cancer metastasis.
Science Advances 2022