Z Gastroenterol 2016; 54 - KV460
DOI: 10.1055/s-0036-1587236

p53 mediates persistent Stat3 activation and contributes to stromal reprogramming in pancreatic cancer in humans and mice

SM Wörmann 1, L Song 1, J Ai 1, N Diakopoulos 1, D Ruess 1, D Jodrell 2, O Sansom 3, T Hagemann 4, MP Protti 5, RM Schmid 1, M Lesina 1, H Algül 1
  • 1II. Medizinische Klinik, Klinikum rechts der Isar, TU München, München, Deutschland
  • 2Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, Cambridge, Großbritannien
  • 3Beatson Institute for Cancer Research, University of Glasgow, Glasgow, Großbritannien
  • 4Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, Großbritannien
  • 5Tumor Immunology Unit, San Raffaele Scientific Institute, Ospedale San Raffaele, Milan, Italy

Background: Stromal reprogramming rather than stromal depletion is emerging as potential major target in patients with pancreatic ductal adenocarcinoma (PDAC). Increasing evidence suggests that persistent signal transducer and activator of transcription 3 (Stat3) activation is involved in the progression of various solid cancers. We hypothesize that functional loss of p53 mediates a new persistent activation-dependent key mechanism in stromal reprogramming through Stat3.

Methods: Various genetically engineered mouse models of pancreatic cancer based on the LSL-Kras G12D knock-in were created. Stat3 expression, p53 accumulation, and Sonic hedgehog (Shh) signaling pathway activation were analyzed in vitro and in vivo in murine and human PDACs. IL6 signaling, trans-signaling, and gp130 ligand dependent Stat3 activation as well as accumulation of reactive oxygen species (ROS) was investigated in vitro. Immune cell infiltration and Th1/Th2 shift was analyzed in vivo and in vitro via cytokine release and FACS analysis. Stromal reprogramming dependent chemoresistance was investigated in various tumor-bearing mice. In a preclinical trial cohorts of mice were treated to assess the therapeutic outcome of persistent Stat3 inhibition.

Results: Loss of p53 in PDAC results in a shift from transient to persistent Stat3 activation through intracellular ROS accumulation, Shp2 inactivation, and prolonged Janus kinase 2 (Jak2) phosphorylation in a gp130 ligand independent manner. Genetic ablation or pharmacological inhibition of persistent Jak2/Stat3 activation significantly reduces stromal elements and reverses the immune escape that leads to therapeutic resistance of PDAC. These findings in mice models are also mirrored in human PDAC tissue specimens.

Conclusion: Our data suggest a novel p53-controlled and Jak2/Stat3-dependent targetable mechanism that is instrumental in stromal reprogramming.