Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer.
Cell Rep. 42:112533 (2023)
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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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
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
Zeitschrift
Cell Reports
Quellenangaben
Band: 42,
Heft: 6,
Artikelnummer: 112533
Verlag
Cell Press
Verlagsort
50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Stem Cell Research (ISF)
Lung Health and Immunity (LHI)
Research Unit Lung Repair and Regeneration (LRR)
Institute of Human Genetics (IHG)
Lung Health and Immunity (LHI)
Research Unit Lung Repair and Regeneration (LRR)
Institute of Human Genetics (IHG)
Förderungen
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
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