Poster Presentation 31st Lorne Cancer Conference 2019

c-Met activation leads to the establishment of a TGFβ receptor regulatory network required for bladder cancer invasion. (#162)

Wen Jin Sim 1 , Prasanna Iyengar 2 , Dilraj Lama 3 , Jean Paul thiery 4 , Pieter Eichhorn 5
  1. Institute of Molecular and Cell Biology, A*STAR, Singapore , Singapore
  2. Cancer Science Institute of Singapore, National University of Singapore, , Singapore
  3. Bioinformatics Institute (A*STAR), , Singapore
  4. Institute of Molecular and Cell Biology, A*STAR, Singapore , Singapore
  5. Curtin University, Bentley, WA, Australia

Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the precise mechanisms underlying HGF/c-MET mediated invasion in bladder cancer remains unknown. To better understand the mechansims underlying HGF induced invasion we compared HGF induced changes in cell plasticity with transcriptiomics. As part of a negative feedback loop SMAD7 binds to the E3 ligase SMURF2 targeting the TGFβ receptor for degradation. Under these conditions SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling by inducing c-SRC-mediated phosphorylation of SMURF2 at two tyrosine residues impeding SMAD7 binding and enhancing SMURF2 C2-HECT domain interaction, resulting in SMURF2 inhibition and TGFβ receptor stabilization. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated Epithelial-Mesenchymal Transition (EMT) and invasion. Using clinically relevant orthotopic mouse models we show that inhibition of TGFβ signalling completely prevents HGF induced bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ receptor kinase and MEK inhibitors in the treatment of high-grade non-muscle-invasive bladder cancers or early stage muscle invasive bladder cancers.