title: Antithetical NFATc1-Sox2 and p53-miR200 signaling networks govern pancreatic cancer cell plasticity.
abstract: 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.
authors.affiliation: Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg, Germany.
authors.forename: Shiv K
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Nai-Ming
authors.initials: NM
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hessmann
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Siveke
authors.affiliation: Institute for Molecular Tumor Biology, Philipps University, Marburg, Germany.
authors.forename: Marlen
authors.initials: M
authors.lastname: Lahmann
authors.affiliation: Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg, Germany.
authors.forename: Garima
authors.initials: G
authors.lastname: Singh
authors.affiliation: Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Voelker
authors.affiliation: Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Vogt
authors.affiliation: Institute of Pathology, Helmholtz Zentrum, Munich, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Institute of Pathology, Philipps University, Marburg, Germany.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Department of Hematology and Oncology, Philipps University, Marburg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brendel
authors.affiliation: Institute for Molecular Tumor Biology, Philipps University, Marburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stiewe
authors.affiliation: Department of Surgery, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.affiliation: Institute for Molecular Tumor Biology, Philipps University, Marburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Mernberger
authors.affiliation: Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, FL, USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.affiliation: Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Bamlet
authors.affiliation: Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Jin-San
authors.initials: JS
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Li
authors.affiliation: Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.affiliation: Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.affiliation: Diabetes Center, USCF, San Francisco, CA, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
authors.affiliation: Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Neesse
authors.affiliation: Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Koenig
authors.affiliation: Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany volker.ellenrieder@med.uni-goettingen.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Ellenrieder
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D050778:NFATC Transcription Factors; D055748:SOXB1 Transcription Factors; D016159:Tumor Suppressor Protein p53
keywords: NFATc1; Sox2; cellular plasticity; miRNA; p53