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bioRxiv · 10.1101/2021.05.26.443198

LMO2 is critical for early metastatic events in breast cancer

Sikandar, S. S.·Antony, J.·Gulati, G. S.·Kuo, A.·Ho, W. H. D.·Das, S.·Steen, C. B.·Pereira, T. A.·Qian, D.·Beachy, P. A.·Dirbas, F.·Red-Horse, K.·Rabbitts, T. H.·Thiery, J. P.·Newman, A. M.·Clarke, M.
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Abstract

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 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 TNF 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. One sentence summaryLMO2 modulates STAT3 signaling in breast cancer metastasis.

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Sikandar, S. S., Antony, J., Gulati, G. S., Kuo, A., Ho, W. H. D., Das, S., Steen, C. B., Pereira, T. A., Qian, D., Beachy, P. A., Dirbas, F., Red-Horse, K., Rabbitts, T. H., Thiery, J. P., Newman, A. M., Clarke, M.. 2021-05-26. LMO2 is critical for early metastatic events in breast cancer. https://doi.org/10.1101/2021.05.26.443198

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