Sim, W.J., Iyengar, P.V., Lama, D. et al. c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression. Nat Commun 10, 4349 (2019). https://doi.org/10.1038/s41467-019-12241-2
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 mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to 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 through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.
This work was funded by research grants from Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR) core funding and Joint Council Office Development Programme 1234e00018, the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative and the Ministry of Education Academic Research Fund Tier 1 grants (T1-2013 Sep-10) and (T1-2014 Oct-08)