Poster Presentation 27th Lorne Cancer Conference 2015

Loss of Slit-Robo signalling in the pancreas increases the severity of pancreatitis (#326)

Andreia V Pinho 1 2 , Marc Giry-Laterriere 3 , Lorraine Chantrill 3 , Amanda Mawson 3 , Maxine Rees 3 , Janet Youkhana 4 , Jianmin Wu 3 , Paul Timpson 3 , Phoebe Phillips 4 , Andrew V Biankin 3 5 , Ilse Rooman 2 3
  1. Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia
  3. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  4. Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales , Sydney, NSW, Australia
  5. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK

Introduction: Genomic analysis of pancreatic tumours revealed that Slit-Robo pathway genes are frequently mutated, hypermethylated or present copy number loss in human pancreatic ductal adenocarcinoma (PDAC)1,2. Our aim is to evaluate if Slit-Robo signalling is implicated in pancreatitis, a condition that predisposes for PDAC.

Materials and Methods: Expression of Slit-Robo genes was analysed in normal mouse pancreas, caerulein-induced acute pancreatitis and Kras/p53 mutant tumours. Mice with loss of critical genes in the Slit-Robo pathway were used for experimental analysis. Pancreatic cells isolated from these animals were cultured using an in vitro method that mimics the events occurring in pancreatitis3 and acute pancreatitis was induced in vivo by treatment with caerulein.

Results: Robo2 is expressed in the exocrine tissue of the normal mouse pancreas, whilst significantly decreased in pancreatitis and nearly lost in PDAC. Exocrine cell cultures with deficiency of Robo2 or its ligand Slit1 present with altered cell adhesion characteristics, upregulation of PDAC precursor markers and activation of pathways involved in pancreatic cancer development such as epithelial to mesenchymal transition and Wnt signalling. Slit1 deficient animals treated with caerulein present with a more severe acute pancreatitis and altered microenvironment, showing an increase in Desmin+ stellate cells and CD3+ positive T lymphocytes.

Discussion: We have found that pancreatic cells with impaired Slit-Robo signalling, upon exposure to stress, either by in vitro culture or in vivo induction of pancreatitis, activate mechanisms that lead to a more severe pancreatitis and that are known to predispose to PDAC. These results constitute the first evidence that loss of Slit-Robo genes may be involved in the early stages of pancreatic cancer development.

  1. Biankin AV et al. Nature, 2012. 491(7424):399-405
  2. Nones K et al. Int J Cancer, 2014. 135(5):1110-8
  3. Pinho AV et al. Gut, 2011. 60(7):958-66