Inflammation-Induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D

Sandra Baumgart, Nai Ming Chen, Jens T. Siveke, Alexander König, Jin San Zhang, Shiv K. Singh, Elmar Wolf, Marek Bartkuhn, Irene Esposito, Elisabeth Heßmann, Johanna Reinecke, Julius Nikorowitsch, Marius Brunner, Garima Singh, Martin E. Fernandez-Zapico, Thomas Smyrk, William R. Bamlet, Martin Eilers, Albrecht Neesse, Thomas M. GressDaniel D. Billadeau, David Tuveson, Raul Urrutia, Volker Ellenrieder

Research output: Contribution to journalArticle

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Abstract

Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote Kras G12D - driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in KrasG12D mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer-promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1-STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials. SIGNIFICANCE: Our study points to the existence of an oncogenic NFATc1-STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1-STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has signifi cant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies.

Original languageEnglish (US)
Pages (from-to)688-701
Number of pages14
JournalCancer discovery
Volume4
Issue number6
DOIs
StatePublished - Jun 2014

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ASJC Scopus subject areas

  • Oncology

Cite this

Baumgart, S., Chen, N. M., Siveke, J. T., König, A., Zhang, J. S., Singh, S. K., Wolf, E., Bartkuhn, M., Esposito, I., Heßmann, E., Reinecke, J., Nikorowitsch, J., Brunner, M., Singh, G., Fernandez-Zapico, M. E., Smyrk, T., Bamlet, W. R., Eilers, M., Neesse, A., ... Ellenrieder, V. (2014). Inflammation-Induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. Cancer discovery, 4(6), 688-701. https://doi.org/10.1158/2159-8290.CD-13-0593