Poster Presentation 31st Lorne Cancer Conference 2019

Predicting mutant p53-dependent pancreatic cancer spread via intravital imaging in the E-cadherin biosensor mouse (#199)

David Herrmann 1 , Zahra Erami 2 , Sean C Warren 1 , Max Nobis 1 , Ewan J McGhee 2 , Morghan C Lucas 1 , Wilfred Leung 1 , Nadine Reischmann 1 , Agata Mrowinska 2 , Juliane P Schwarz 2 , Shereen Kadir 2 , James RW Conway 1 , Claire Vennin 1 , Saadia A Karim 2 , Andrew D Campbell 2 , David Gallego-Ortega 1 , Astrid Magenau 1 , Kendelle J Murphy 1 , Rachel A Ridgway 2 , Andrew M Law 1 , Stacey N Walters 1 , Shane T Grey 1 , David R Croucher 1 , Lei Zhang 1 , Herbert Herzog 1 , Edna C Hardeman 3 , Peter W Gunning 4 , Christopher J Ormandy 1 , Jeffry Evans 2 , Douglas Strathdee 2 , Owen J Sansom 2 , Jennifer P Morton 2 , Kurt I Anderson 2 , Paul Timpson 1
  1. Garvan Institute / The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
  2. Cancer Research UK Beatson Institute, Glasgow, UK
  3. Neuromuscular and Regenerative Medicine Unit, School of Medical Sciences, University of New South Wales, Sydney, Australia
  4. Oncology Research Unit, School of Medical Sciences, University of New South Wales, Sydney, Sydney, NSW, Australia

The disruption of E-cadherin-mediated cell-cell junctions is known to play an important role in cancer invasion and metastasis. Here, we have generated an E-cadherin-GFP mouse, which enables intravital photobleaching (FRAP) and quantification of E-cadherin mobility in live tissue. We assessed E-cadherin mobility in native pancreatic tissue or upon genetic manipulation involving Kras and p53, both of which are commonly mutated in pancreatic cancer patients. In particular, we demonstrate that while KrasG12D mutation alone or in combination with loss of p53 has no effect on E-cadherin mobility, the acquisition of both KrasG12D and p53R172H mutations leads to the mobilization of E-cadherin within tumour cell-cell junctions to drive invasive behavior. We correlate our results with a loss of cell-cell junction strength and integrity in invasive mutant p53 tumor cell lines and show that E-cadherin mobilization can be targeted with anti-invasive treatment. Our E-cadherin-GFP mouse may thus be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments. Future intravital FRAP imaging through titanium windows in the same mouse over the course of tumour progression will allow us to identify hotspots of tumour dissolution events to predict early cancer spread.