The influence of NFATc1 on the inflammatory tumor environment in pancreatic carcinogenesis

Introduction: Pancreatic ductal adenocarcinoma (PDAC) formation and progression requires constitutive activation of oncogenic Kras. The impact of constitutive Kras activation is not limited on epithelial cell but also participates in the modulation of the tumor environment. Latest studies revealed that even early stages of carcinogenesis are associated with a stromal reaction, characterized by a robust desmoplastic response and recruitment of immune cells.

Recent evidence suggests an important role for the inflammatory transcription factor NFATc1 in pancreatic carcinogenesis but its influence on the composition of the tumor environment remains unclear.

Aim: To analyze whether and how NFATc1 modulates the cross-talk between PDAC precursor lesions and the inflammatory tumor environment.

Methods: Transgenic mice with wildtype expression or conditional knockout of NFATc1 on the background of activated Kras were sacrificed at different time points. Gene expression in mice tissue was determined by using quantitative RT-PCR, immunoblotting and immunohistochemical stainings. By flow cytometry, different stromal cell populations were defined while ELISA was used to analyse cytokine and chemokine profiles in pancreatic tissue.

Results: The stromal composition and inflammatory response during pancreatic carcinogenesis is significantly modified depending on the NFATc1 presence or absence. NFATc1 knockout resulted in a delay of PDAC precursor lesion formation. The changes in stromal composition are accompanied by NFAT-dependent differences in cytokine and chemokine expression.

Conclusion: Our data provide first evidence that NFATc1 accelerates pancreatic carcinogenesis by cooperating with oncogenic Kras in modulation of the tumor environment. Thus, NFATc1 inactivation is a promising tool for new therapeutic options in PDAC treatment.

Akute Pankreatitis

Donnerstag, 18. September 2014/15:00 – 16:30/Saal Werner Creutzfeldt