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Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer

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Item Type:Article
Title:Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer
Creators Name:Saini, M. and Schmidleitner, L. and Moreno, H.D. and Donato, E. and Falcone, M. and Bartsch, J.M. and Vogel, V. and Würth, R. and Pfarr, N. and Espinet, E. and Lehmann, M. and Königshoff, M. and Reitberger, M. and Haas, S. and Graf, E. and Schwarzmayr, T. and Strom, T.M. and Spaich, S. and Sütterlin, M. and Schneeweiss, A. and Weichert, W. and Schotta, G. and Reichert, M. and Aceto, N. and Sprick, M.R. and Trumpp, A. and Scheel, C.H. and Klein, C.
Abstract: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:EPCAM, EMT, ZEB1, GRHL2, Breast Cancer, Metastasis, Intratumor Heterogeneity
Source:Cell Reports
Publisher:Cell Press / Elsevier
Page Range:112533
Date:27 June 2023
Official Publication:https://doi.org/10.1016/j.celrep.2023.112533
PubMed:View item in PubMed

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