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TYRO3 as a molecular target for growth inhibition and apoptosis induction in bladder cancer
Florent Dufour1,2, Linda Silina1,2, Hélène Neyret-Kahn1,2
1Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, 75005, Paris, France.
Background:
Muscle-invasive bladder cancer (MIBC) is an aggressive neoplasm with poor prognosis, lacking effective therapeutic targets. Oncogenic dependency on members of the TAM tyrosine kinase receptor family (TYRO3, AXL, MERTK) has been reported in several cancer types, but their role in bladder cancer has never been explored.
Methods:
TAM receptor expression was evaluated in two series of human bladder tumours by gene expression (TCGA and CIT series), immunohistochemistry and western blotting analyses (CIT series). The role of the different TAM receptors was assessed by loss-of-function experiments and pharmaceutical inhibition in vitro and in vivo.
Results:
We reported a significantly higher expression of TYRO3, but not AXL or MERTK, in both non-MIBCs and MIBCs, compared to normal urothelium. Loss-of-function experiments identified a TYRO3-dependency of bladder carcinoma-derived cells both in vitro and in a mouse xenograft model, whereas AXL and MERTK depletion had only a minor impact on cell viability. Accordingly, TYRO3-dependent bladder tumour cells were sensitive to pharmacological treatment with two pan-TAM inhibitors. Finally, growth inhibition upon TYRO3 depletion relies on cell cycle inhibition and apoptosis associated with induction of tumour-suppressive signals.
Conclusions:
Our results provide a preclinical proof of concept for TYRO3 as a potential therapeutic target in bladder cancer.
Insights
This study reveals TYRO3 receptor tyrosine kinase is overexpressed in bladder cancer and crucial for tumor cell growth. Inhibiting TYRO3 shows promise as a new therapeutic strategy for muscle-invasive bladder cancer (MIBC).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Muscle-invasive bladder cancer (MIBC) is aggressive with poor prognosis and lacks effective treatments.
- The role of TAM receptor tyrosine kinases (TYRO3, AXL, MERTK) in bladder cancer remains unexplored.
- Oncogenic dependencies on TAM receptors are known in other cancers.
Purpose of the Study:
- To investigate the expression and function of TAM receptors in bladder cancer.
- To determine if TYRO3, AXL, or MERTK could be potential therapeutic targets for MIBC.
Main Methods:
- Evaluated TAM receptor expression in human bladder tumors using gene expression, immunohistochemistry, and western blotting.
- Performed loss-of-function experiments and pharmaceutical inhibition in vitro and in vivo.
- Assessed the impact of TYRO3, AXL, and MERTK depletion on bladder cancer cell viability.
Main Results:
- TYRO3 expression was significantly higher in non-MIBCs and MIBCs compared to normal urothelium.
- Bladder cancer cells exhibited TYRO3-dependency, while AXL and MERTK had minimal impact.
- TYRO3-dependent cells responded to pan-TAM inhibitors, with TYRO3 depletion inducing cell cycle arrest and apoptosis.
Conclusions:
- TYRO3 is a potential therapeutic target for bladder cancer.
- Preclinical data support TYRO3 inhibition as a viable treatment strategy for MIBC.
- Further research into TYRO3-targeted therapies for bladder cancer is warranted.
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