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Differential contributions of pre- And post-EMT tumor cells in breast cancer metastasis

Lourenco, AR and Ban, Y and Crowley, MJ and Lee, SB and Ramchandani, D and Du, W and Elemento, O and George, JT and Jolly, MK and Levine, H and Sheng, J and Wong, ST and Altorki, NK and Gao, D (2020) Differential contributions of pre- And post-EMT tumor cells in breast cancer metastasis. In: Cancer Research, 80 (2). pp. 163-169.

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Official URL: https://dx.doi.org/10.1158/0008-5472.CAN-19-1427


Metastases are responsible for the majority of breast cancer�associated deaths. The contribution of epithelial-to-mesenchymal transition (EMT) in the establishment of metastases is still controversial. To obtain in vivo evidence of EMT in metastasis, we established an EMT lineage tracing (Tri-PyMT) model, in which tumor cells undergoing EMT would irreversibly switch their fluorescent marker from RFPþ to GFPþ due to mesenchymal-specific Cre expression. Surprisingly, we found that lung metastases were predominantly derived from the epithelial compartment of breast tumors. However, concerns were raised on the fidelity and sensitivity of RFP-to-GFP switch of this model in reporting EMT of metastatic tumor cells. Here, we evaluated Tri-PyMT cells at the single-cell level using single-cell RNA-sequencing and found that the Tri-PyMT cells exhibited a spectrum of EMT phenotypes, with EMT-related genes concomitantly expressed with the activation of GFP. The fluorescent color switch in these cells precisely marked an unequivocal change in EMT status, defining the pre-EMT and post-EMT compartments within the tumor. Consistently, the pre-EMT cells played dominant roles in metastasis, while the post-EMT cells were supportive in promoting tumor invasion and angiogenesis. Importantly, the post-EMT (GFPþ) cells in the Tri-PyMT model were not permanently committed to the mesenchymal phenotype; they were still capable of reverting to the epithelial phenotype and giving rise to secondary tumors, suggesting their persistent EMT plasticity. Our study addressed major concerns with the Tri-PyMT EMT lineage tracing model, which provides us with a powerful tool to investigate the dynamic EMT process in tumor biology.

Item Type: Journal Article
Publication: Cancer Research
Publisher: American Association for Cancer Research Inc.
Additional Information: Copyright of this article belongs to American Association for Cancer Research Inc.
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 28 Jan 2020 08:48
Last Modified: 28 Jan 2020 08:48
URI: http://eprints.iisc.ac.in/id/eprint/64424

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