Poster Presentation 35th Lorne Cancer Conference 2023

Using E-cadherin dynamics and Src activity to predict cancer spread and response to anti-invasive therapies. (#160)

Daniel A Reed 1 2 , Sean C Warren 1 2 , Max Nobis 1 2 , Kendelle J Murphy 1 2 , Astrid Magenau 1 2 , Claire Vennin 1 2 , Lilian Schimmel 3 , Daryan Kempe 2 , Mojca Hribersek 1 , Michael Trpceski 1 2 , Cecilia R Chambers 1 2 , Jordan Hastings 1 2 , Stacey N Walters 1 , Aurelie S Cazet 1 2 , Marcia Munoz 1 2 , Andrius Masedunskas 2 , David Gallego-Ortega 1 2 , Shane T Grey 1 2 , Herbert Herzog 1 2 , Mate Biro 2 , David R Croucher 1 2 , Emma Gordon 3 , Yingxiao Wang 4 , Jennifer P Morton 5 , Owen J Sansom 5 , Douglas Strathdee 5 , Jody J Haigh 6 , Paul Timpson 1 2 , David Herrmann 1 2
  1. Garvan Institute / The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
  2. UNSW Sydney, Sydney, NSW, Australia
  3. The University of Queensland, St Lucia, QLD, Australia
  4. Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA
  5. Cancer Research UK Beatson Institute, Glasgow, UK
  6. Monash University, Clayton

Background: E-cadherin-mediated cell-cell junctions play a prominent role in maintaining epithelial architecture. Their dysregulation in cancer can lead to the collapse of tumour epithelia and subsequent invasion and metastasis. Recent evidence suggests that, apart from modulating E-cadherin expression, cells are able to mobilise E-cadherin within their cell-cell junctions upon migration and invasion. We have developed new tools to assess the spatiotemporal dynamics of epithelial tumour cell-cell junctions and also to assess Src kinase activity to study early stages of invasion and metastasis.


Methods: Here, we have generated an endogenous E-cadherin-GFP mouse, which enables intravital imaging and quantification of E-cadherin dynamics to provide insight into tumour cell-cell junction strength and integrity in intact tissues and tumours. In addition, we have generated a Src kinase biosensor mouse to track changes in Src activity, a known driver of cancer invasion and metastasis.


Results:  We reveal that:

(1) E-cadherin dynamics become de-regulated in invasive and metastatic tumours compared to healthy tissues and non-invasive pancreatic tumours.

(2) These subcellular aberrations in E-cadherin dynamics can be targeted with anti-invasive treatment to re-stabilise cell-cell junctions and to reduce cancer invasiveness.

(3) Using a Src biosensor mouse we can track in real-time in native tissue, changes in Src activity, during cancer development and subsequent metastasis.


Discussion: We suggest that these techniques can be used as:

(1) versatile models to assess cell-cell junction dynamics and Src activation in a broad range of contexts highlighting the wider applications of our technology

(2) novel tools to fundamentally expand our understanding of cancer spread in vivo in native microenvironments.

(3) novel pre-clinical drug-screening platform to predict cancer spread and to estimate the efficacy of anti-invasive treatment.