Differential Contributions of Pre- and Post-EMT Tumor Cells in Breast Cancer Metastasis.

TitleDifferential Contributions of Pre- and Post-EMT Tumor Cells in Breast Cancer Metastasis.
Publication TypeJournal Article
Year of Publication2020
AuthorsLourenco ARita, Ban Y, Crowley MJ, Lee SB, Ramchandani D, Du W, Elemento O, George JT, Jolly MKumar, Levine H, Sheng J, Wong ST, Altorki NK, Gao D
JournalCancer Res
Date Published2020 01 15
KeywordsBreast Neoplasms, Cell Line, Tumor, Epithelial-Mesenchymal Transition, Humans, Lung Neoplasms, Phenotype

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 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 RFP to GFP 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 (GFP) 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. SIGNIFICANCE: These findings confirm the fidelity and sensitivity of the EMT lineage tracing (Tri-PyMT) model and highlight the differential contributions of pre- and post-EMT tumor cells in breast cancer metastasis..

Alternate JournalCancer Res.
PubMed ID31704888
PubMed Central IDPMC6980649
Grant ListR01 CA205418 / CA / NCI NIH HHS / United States
U01 CA188388 / CA / NCI NIH HHS / United States