c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression

Wen Jing Sim, Prasanna Vasudevan Iyengar, Dilraj Lama, Sarah Kit Leng Lui, Hsien Chun Ng, Lior Haviv-Shapira, Eytan Domany, Dennis Kappei, Tuan Zea Tan, Azad Saei, Patrick William Jaynes, Chandra Shekhar Verma, Alan Prem Kumar, Mathieu Rouanne, Hong Koo Ha, Camelia Radulescu, Peter ten Dijke, Pieter Johan Adam Eichhorn () and Jean Paul Thiery ()
Additional contact information
Wen Jing Sim: Institute of Molecular and Cell Biology, A*STAR
Prasanna Vasudevan Iyengar: National University of Singapore
Dilraj Lama: Bioinformatics Institute (A*STAR)
Sarah Kit Leng Lui: National University of Singapore
Hsien Chun Ng: Institute of Molecular and Cell Biology, A*STAR
Lior Haviv-Shapira: The Weizmann Institute of Science
Eytan Domany: The Weizmann Institute of Science
Dennis Kappei: National University of Singapore
Tuan Zea Tan: National University of Singapore
Azad Saei: National University of Singapore
Patrick William Jaynes: National University of Singapore
Chandra Shekhar Verma: Bioinformatics Institute (A*STAR)
Alan Prem Kumar: National University of Singapore
Mathieu Rouanne: Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay
Hong Koo Ha: Pusan National University Hospital, Pusan National University School of Medicine
Camelia Radulescu: Université Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay
Peter ten Dijke: Leiden University Medical Center
Pieter Johan Adam Eichhorn: National University of Singapore
Jean Paul Thiery: Institute of Molecular and Cell Biology, A*STAR

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12241-2

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