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

Ana Rita Lourenco, Yi Ban, Michael J. Crowley, Sharrell B. Lee, Divya Ramchandani, Wei Du, Olivier Elemento, Jason T. George, Mohit Kumar Jolly, Herbert Levine, Jianting Sheng, Stephen T. Wong, Nasser K. Altorki, Dingcheng Gao

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)163-169
Number of pages7
JournalCancer research
Volume80
Issue number2
DOIs
StatePublished - 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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