Aberrant NFATc1 signaling counteracts TGFβ-mediated growth arrest and apoptosis induction in pancreatic cancer progression

Abstract

Given its aggressive tumor biology and its exceptional therapy resistance, pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine and is characterized by a 5-year survival rate of <8%. At the cellular level, PDAC is largely driven by the activation of signaling pathways that eventually converge in altered, tumor-promoting transcription programs. In this study, we sought to determine the interplay between transforming growth factor β (TGFβ) signaling and activation of the inflammatory transcription factor nuclear factor of activated T cells (NFATc1) in the regulation of transcriptional programs throughout PDAC progression. Genome-wide transcriptome analysis and functional studies performed in primary PDAC cells and transgenic mice linked nuclear NFATc1 expression with pro-proliferative and anti-apoptotic gene signatures. Consistently, NFATc1 depletion resulted in downregulation of target genes associated with poor PDAC outcome and delayed pancreatic carcinogenesis in vivo. In contrast to previous reports and consistent with a concept of retained tumor suppressive TGFβ activity, even in established PDAC, TGFβ treatment reduced PDAC cell proliferation and promoted apoptosis even in the presence of oncogenic NFATc1. However, combined TGFβ treatment and NFATc1 depletion resulted in a tremendous abrogation of tumor-promoting gene signatures and functions. Chromatin studies implied that TGFβ-dependent regulators compete with NFATc1 for the transcriptional control of jointly regulated target genes associated with an unfavorable PDAC prognosis. Together, our findings suggest opposing consequences of TGFβ and NFATc1 activity in the regulation of pro-tumorigenic transcription programs in PDAC and emphasize the strong context-dependency of key transcription programs in the progression of this devastating disease.