TY  - JOUR
AU  - Saini, Massimo
AU  - Schmidleitner, Laura
AU  - Moreno, Helena Domínguez
AU  - Donato, Elisa
AU  - Falcone, Mattia
AU  - Bartsch, Johanna M
AU  - Vogel, Vanessa
AU  - Würth, Roberto
AU  - Pfarr, Nicole
AU  - Espinet, Elisa
AU  - Lehmann, Mareike
AU  - Königshoff, Melanie
AU  - Reitberger, Manuel
AU  - Haas, Simon
AU  - Graf, Elisabeth
AU  - Schwarzmayr, Thomas
AU  - Strom, Tim-Matthias
AU  - Spaich, Saskia
AU  - Sütterlin, Marc
AU  - Schneeweiss, Andreas
AU  - Weichert, Wilko
AU  - Schotta, Gunnar
AU  - Reichert, Maximilian
AU  - Aceto, Nicola
AU  - Sprick, Martin
AU  - Trumpp, Andreas
AU  - Scheel, Christina H
AU  - Klein, Corinna
TI  - Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer.
JO  - Cell reports
VL  - 42
IS  - 6
SN  - 2211-1247
CY  - [New York, NY]
PB  - Elsevier
M1  - DKFZ-2023-01077
SP  - 112533
PY  - 2023
N1  - DKFZ-ZMBH Alliance / #EA:A010#LA:A010# / 2023 Jun 27;42(6):112533
AB  - 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.
KW  - CP: Cancer (Other)
KW  - EMT (Other)
KW  - EPCAM (Other)
KW  - GRHL2 (Other)
KW  - ZEB1 (Other)
KW  - breast cancer (Other)
KW  - intratumor heterogeneity (Other)
KW  - metastasis (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37257449
DO  - DOI:10.1016/j.celrep.2023.112533
UR  - https://inrepo02.dkfz.de/record/276368
ER  -