Identification of a minority population of LMO2+ breast cancer cells that integrate into the vasculature and initiate metastasis.
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Date
2022-11-11ICR Author
Author
Sikandar, SS
Gulati, GS
Antony, J
Fetter, I
Kuo, AH
Ho, WHD
Haro-Acosta, V
Das, S
Steen, CB
Pereira, TA
Qian, D
Beachy, PA
Dirbas, FM
Red-Horse, K
Rabbitts, TH
Thiery, JP
Newman, AM
Clarke, MF
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Mice
Animals
Female
Breast Neoplasms
Lung Neoplasms
Signal Transduction
Proto-Oncogene Proteins
Adaptor Proteins, Signal Transducing
LIM Domain Proteins
Research team
Chr Trans & Intra Ab Ther
Language
eng
Date accepted
2022-09-22
License start date
2022-11-11
Citation
Science Advances, 2022, 8 (45), pp. eabm3548 -
Publisher
AMER ASSOC ADVANCEMENT SCIENCE