Journal
SCIENCE ADVANCES
Volume 8, Issue 45, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abm3548
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Funding
- NIH/NCI [U01CA154209-01, P01 CA139490-05]
- Breast Cancer Research Foundation
- U.S. Department of Defense [W81XWH-11-1-0287, W81XWH-13-1-0281, W81XWH-12-1-0020]
- National Cancer Institute [R0490CA187192-03, R01CA255450, 5R01CA100225-09]
- National Cancer Institute (PHS) [CA09302]
- Stanford Bio-X Interdisciplinary Initiatives Seed Grants Program (IIP)
- Virginia and D.K. Ludwig Fund for Cancer Research
- Stinehart-Reed Foundation
- Donald E. and Delia B. Baxter Foundation
- Stanford School of Medicine Dean's Fellowship
- Stanford Bio-X Bowes Graduate Student Fellowship
- Stanford Medical Science Training Program
- NIH/NHLBI [R01-HL128503]
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A minority population of immature tumor epithelial cells with angiogenic features, marked by the oncogene LMO2, has been identified in human breast tumor biopsies. Higher abundance of LMO2(+) basal cells is correlated with tumor endothelial content and predicts poor prognosis. LMO2 binds to STAT3 and is required for STAT3 activation, promoting breast cancer metastasis.
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/Lmo2(CreERT2) 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-alpha 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.
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