Premium
Antithetical NFAT c1–Sox2 and p53–miR200 signaling networks govern pancreatic cancer cell plasticity
Author(s) -
Singh Shiv K,
Chen NaiMing,
Hessmann Elisabeth,
Siveke Jens,
Lahmann Marlen,
Singh Garima,
Voelker Nadine,
Vogt Sophia,
Esposito Irene,
Schmidt Ansgar,
Brendel Cornelia,
Stiewe Thorsten,
Gaedcke Jochen,
Mernberger Marco,
Crawford Howard C,
Bamlet William R,
Zhang JinSan,
Li XiaoKun,
Smyrk Thomas C,
Billadeau Daniel D,
Hebrok Matthias,
Neesse Albrecht,
Koenig Alexander,
Ellenrieder Volker
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201489574
Subject(s) - biology , nfat , microbiology and biotechnology , sox2 , signal transduction , pancreatic cancer , cancer research , cancer , genetics , transcription factor , gene
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 NFAT c1 as a central regulator of pancreatic cancer cell plasticity. In particular, we show that NFAT c1 drives EMT reprogramming and maintains pancreatic cancer cells in a stem cell‐like state through Sox2‐dependent transcription of EMT and stemness factors. Intriguingly, NFAT c1–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 NFAT c1 signaling activities.