Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer

Cell Rep. 2023 Jun 27;42(6):112533. doi: 10.1016/j.celrep.2023.112533. Epub 2023 May 30.


The acquisition of mesenchymal traits is considered a hallmark of breast cancer progression. However, the functional relevance of epithelial-to-mesenchymal transition (EMT) remains controversial and context dependent. Here, we isolate epithelial and mesenchymal populations from human breast cancer metastatic biopsies and assess their functional potential in vivo. Strikingly, progressively decreasing epithelial cell adhesion molecule (EPCAM) levels correlate with declining disease propagation. Mechanistically, we find that persistent EPCAM expression marks epithelial clones that resist EMT induction and propagate competitively. In contrast, loss of EPCAM defines clones arrested in a mesenchymal state, with concomitant suppression of tumorigenicity and metastatic potential. This dichotomy results from distinct clonal trajectories impacting global epigenetic programs that are determined by the interplay between human ZEB1 and its target GRHL2. Collectively, our results indicate that susceptibility to irreversible EMT restrains clonal propagation, whereas resistance to mesenchymal reprogramming sustains disease spread in multiple models of human metastatic breast cancer, including patient-derived cells in vivo.

Keywords: CP: Cancer; EMT; EPCAM; GRHL2; ZEB1; breast cancer; intratumor heterogeneity; metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast / metabolism
  • Breast Neoplasms* / pathology
  • Cell Line, Tumor
  • Clone Cells / metabolism
  • Epithelial Cell Adhesion Molecule
  • Epithelial-Mesenchymal Transition
  • Female
  • Humans


  • Epithelial Cell Adhesion Molecule