A cell autonomous EGFR-NFATc1 loop promotes acinar to ductal metaplasia in pancreatic carcinogenesis
Introduction: Recent evidence has shown a crucial role for EGFR activation in KrasG12 D -driven pancreatic carcinogenesis. However, the key transcription pathways conferring EGFR signalling in early tumorigenesis are enigmatic.
Aims: To define signaling networks in EGFR driven ADM formation in vitro and in vivo.
Methods: KrasG12 D mice strains with pancreas specific differential NFATc1 activation were challenged by chronic pancreatitis. Acinar cells were isolated from KrasG12D or KrasG12 D-NFATc1fl/fl mice and treated with EGF (20 ng/ml). Pancreata and acinar cell explants were analysed by IHC, RT-PCR and WB. ChIP-seq and microarray tools were performed to identify NFATc1 target genes and co-immunoprecipitation was carried out to identify NFATc1 transcription partner.
Results: We identified an cell-autonomous EGFR-NFATc1 loop in ADM formation. Furthermore, genetic depletion of NFATc1 reduced EGFR expression and signaling and thwarted ADM formation in KrasG12 D mice, even in context of chronic inflammation. Mechanistically, EGFR induces NFATc1 and c-Jun transcription complex formation on consequent Sox9 promoter induction, a key step in ADM formation.
Conclusion: Our study uncovers an cell-autonomous EGFR-NFATc1 signaling loop which is required for pancreatic cancer initiation.