NFATc1 links EGFR signaling to induction of sox9 transcription and acinar-ductal transdifferentiation in the pancreas

Nai Ming Chen, Garima Singh, Alexander Koenig, Geou Yarh Liou, Peter Storz, Jin San Zhang, Lisanne Regul, Sankari Nagarajan, Benjamin Kühnemuth, Steven Johnsen, Matthias Hebrok, Jens Siveke, Daniel D Billadeau, Volker Ellenrieder, Elisabeth Hessmann

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Background & Aims Oncogenic mutations in KRAS contribute to the development of pancreatic ductal adenocarcinoma, but are not sufficient to initiate carcinogenesis. Secondary events, such as inflammation-induced signaling via the epidermal growth factor receptor (EGFR) and expression of the SOX9 gene, are required for tumor formation. Herein we sought to identify the mechanisms that link EGFR signaling with activation of SOX9 during acinar-ductal metaplasia, a transdifferentiation process that precedes pancreatic carcinogenesis. Methods We analyzed pancreatic tissues from Kras<sup>G12D</sup>;pdx1-Cre and Kras<sup>G12D</sup>;NFATc1<sup>Δ/Δ</sup>;pdx1-Cre mice after intraperitoneal administration of caerulein, vs cyclosporin A or dimethyl sulfoxide (controls). Induction of EGFR signaling and its effects on the expression of Nuclear factor of activated T cells c1 (NFATc1) or SOX9 were investigated by quantitative reverse-transcription polymerase chain reaction, immunoblot, and immunohistochemical analyses of mouse and human tissues and acinar cell explants. Interactions between NFATc1 and partner proteins and effects on DNA binding or chromatin modifications were studied using co-immunoprecipitation and chromatin immunoprecipitation assays in acinar cell explants and mouse tissue. Results EGFR activation induced expression of NFATc1 in metaplastic areas from patients with chronic pancreatitis and in pancreatic tissue from Kras<sup>G12D</sup> mice. EGFR signaling also promoted formation of a complex between NFATc1 and C-JUN in dedifferentiating mouse acinar cells, leading to activation of Sox9 transcription and induction of acinar-ductal metaplasia. Pharmacologic inhibition of NFATc1 or disruption of the Nfatc1 gene inhibited EGFR-mediated induction of Sox9 transcription and blocked acinar-ductal transdifferentiation and pancreatic cancer initiation in mice. Conclusions EGFR signaling induces expression of NFATc1 and Sox9, leading to acinar cell transdifferentiation and initiation of pancreatic cancer. Strategies designed to disrupt this pathway might be developed to prevent pancreatic cancer initiation in high-risk patients with chronic pancreatitis.

Original languageEnglish (US)
Pages (from-to)1024-1034.e9
JournalGastroenterology
Volume148
Issue number5
DOIs
StatePublished - May 1 2015

Keywords

  • ChIP
  • Gene Regulation
  • Mouse Model
  • Signal Transduction

ASJC Scopus subject areas

  • Gastroenterology

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    Chen, N. M., Singh, G., Koenig, A., Liou, G. Y., Storz, P., Zhang, J. S., Regul, L., Nagarajan, S., Kühnemuth, B., Johnsen, S., Hebrok, M., Siveke, J., Billadeau, D. D., Ellenrieder, V., & Hessmann, E. (2015). NFATc1 links EGFR signaling to induction of sox9 transcription and acinar-ductal transdifferentiation in the pancreas. Gastroenterology, 148(5), 1024-1034.e9. https://doi.org/10.1053/j.gastro.2015.01.033