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Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer

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 m...

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Main Authors: Saini, Massimo (Author) , Schmidleitner, Laura (Author) , Domínguez Moreno, Helena (Author) , Donato, Elisa (Author) , Falcone, Mattia (Author) , Bartsch, Johanna M. (Author) , Klein, Corinna (Author) , Vogel, Vanessa (Author) , Würth, Roberto (Author) , Pfarr, Nicole (Author) , Espinet, Elisa (Author) , Lehmann, Mareike (Author) , Königshoff, Melanie (Author) , Reitberger, Manuel (Author) , Haas, Simon (Author) , Graf, Elisabeth (Author) , Schwarzmayr, Thomas (Author) , Strom, Tim-Matthias (Author) , Spaich, Saskia (Author) , Sütterlin, Marc (Author) , Schneeweiss, Andreas (Author) , Weichert, Wilko (Author) , Schotta, Gunnar (Author) , Reichert, Maximilian (Author) , Aceto, Nicola (Author) , Sprick, Martin (Author) , Trumpp, Andreas (Author) , Scheel, Christina H. (Author)
Format: Article (Journal)
Language:English
Published: 30 May 2023
In: Cell reports
Year: 2023, Volume: 42, Issue: 6
ISSN:2211-1247
DOI:10.1016/j.celrep.2023.112533
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.celrep.2023.112533
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2211124723005442
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Author Notes:Massimo Saini, Laura Schmidleitner, Helena Domínguez Moreno, Elisa Donato, Mattia Falcone, Johanna M. Bartsch, Corinna Klein, Vanessa Vogel, Roberto Würth, Nicole Pfarr, Elisa Espinet, Mareike Lehmann, Melanie Königshoff, Manuel Reitberger, Simon Haas, Elisabeth Graf, Thomas Schwarzmayr, Tim-Matthias Strom, Saskia Spaich, Marc Sütterlin, Andreas Schneeweiss, Wilko Weichert, Gunnar Schotta, Maximilian Reichert, Nicola Aceto, Martin R. Sprick, Andreas Trumpp, Christina H. Scheel

MARC

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520 |a 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. 
650 4 |a Breast 
650 4 |a breast cancer 
650 4 |a Breast Neoplasms 
650 4 |a Cell Line, Tumor 
650 4 |a Clone Cells 
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650 4 |a EMT 
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650 4 |a Female 
650 4 |a GRHL2 
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650 4 |a metastasis 
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