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Singh, S.K.* ; Chen, N.M.* ; Hessmann, E.* ; Siveke, J.* ; Lahmann, M.* ; Singh, G.* ; Voelker, N.* ; Vogt, S.* ; Esposito, I. ; Schmidt, A.* ; Brendel, C.* ; Stiewe, T.* ; Gaedcke, J.* ; Merenberger, M.* ; Crawford, H.C.* ; Bamlet, W.R.* ; Zhang, J.S.* ; Li, X.K.* ; Smyrk, T.C.* ; Billadeau, D.D.* ; Hebrok, M.* ; Neesse, A.* ; Koenig, A.* ; Ellenrieder, V.*

Antithetical NFATc1-Sox2 and p53-miR200 signaling networks govern pancreatic cancer cell plasticity.

EMBO J. 34, 517-530 (2015)
Verlagsversion DOI PMC
Open Access Gold
In adaptation to oncogenic signals, pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial-mesenchymal transition (EMT), a process combining tumor cell dedifferentiation with acquisition of stemness features. However, the mechanisms linking oncogene-induced signaling pathways with EMT and stemness remain largely elusive. Here, we uncover the inflammation-induced transcription factor NFATc1 as a central regulator of pancreatic cancer cell plasticity. In particular, we show that NFATc1 drives EMT reprogramming and maintains pancreatic cancer cells in a stem cell-like state through Sox2-dependent transcription of EMT and stemness factors. Intriguingly, NFATc1-Sox2 complex-mediated PDAC dedifferentiation and progression is opposed by antithetical p53-miR200c signaling, and inactivation of the tumor suppressor pathway is essential for tumor dedifferentiation and dissemination both in genetically engineered mouse models (GEMM) and human PDAC. Based on these findings, we propose the existence of a hierarchical signaling network regulating PDAC cell plasticity and suggest that the molecular decision between epithelial cell preservation and conversion into a dedifferentiated cancer stem cell-like phenotype depends on opposing levels of p53 and NFATc1 signaling activities.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Nfatc1 ; Sox2 ; Cellular Plasticity ; Mirna ; P53
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Zeitschrift EMBO Journal, The
Quellenangaben Band: 34, Heft: 4, Seiten: 517-530 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Heidelberg, Germany
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pathology (PATH)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-500300-001
PubMed ID 25586376
DOI 10.15252/embj.201489574
Scopus ID 84923050071
Erfassungsdatum 2015-01-16
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