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Saini, M. ; Schmidleitner, L. ; Moreno, H.D.* ; Donato, E.* ; Falcone, M.* ; Bartsch, J. ; Klein, C.* ; Vogel, V.* ; Würth, R.* ; Pfarr, N.* ; Espinet, E.* ; Lehmann, M. ; Königshoff, M. ; Reitberger, M.* ; Haas, S.* ; Graf, E. ; Schwarzmayr, T. ; Strom, T.M. ; Spaich, S.* ; Sütterlin, M.* ; Schneeweiss, A.* ; Weichert, W.* ; Schotta, G.* ; Reichert, M.* ; Aceto, N.* ; Sprick, M.R.* ; Trumpp, A.* ; Scheel, C.

Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer.

Cell Rep. 42:112533 (2023)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cp: Cancer ; Emt ; Epcam ; Grhl2 ; Zeb1 ; Breast Cancer ; Intratumor Heterogeneity ; Metastasis; Tumor-initiating Cells; Feedback Loop; Stem-cell; Lung Metastasis; E-cadherin; Emt; Transition; Plasticity; Chromatin; Zeb1
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 42, Issue: 6, Pages: , Article Number: 112533 Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Stem Cell Research (ISF)
Lung Health and Immunity (LHI)
Research Unit Lung Repair and Regeneration (LRR)
Institute of Human Genetics (IHG)
Grants Swiss Bridge Award
Dietmar Hopp Foundation
Max Eder Grant of the German Cancer Aid Organisation (Deutsche Kreb-shilfe)
German Cancer Aid Organisation (Max-Eder Program)
German Research Foundation (DFG)
Federal Ministry of Education and Research, SATURN3 "Spatial and Temporal Resolution of Intratumoral Heterogeneity in 3 hard-to-treat Cancers
Deutsche Forschungsgemeinschaft (DFG
German Cancer Aid Organisation (Translational Oncology Program)
German Research Foundation)
European Research Council
ETH Zurich
strategic focus area of Personalized Health and Related Technologies at ETH Zurich
Future and Emerging Technologies programme of the European Commission
Swiss National Science Foundation
Swiss Cancer League
ETH Lymphoma Challenge