TYRO3 as a molecular target for growth inhibition and apoptosis induction in bladder cancer.
Animals
Apoptosis
/ genetics
Carcinoma, Transitional Cell
/ genetics
Cell Line, Tumor
Cell Survival
Gene Expression
Humans
Hylobatidae
Immunochemistry
In Vitro Techniques
Mice
Molecular Targeted Therapy
Muscle, Smooth
/ pathology
Neoplasm Invasiveness
Neoplasm Transplantation
Proto-Oncogene Proteins
/ genetics
Receptor Protein-Tyrosine Kinases
/ genetics
Urinary Bladder Neoplasms
/ genetics
c-Mer Tyrosine Kinase
/ genetics
Axl Receptor Tyrosine Kinase
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
02
05
2018
accepted:
22
01
2019
revised:
18
12
2018
pubmed:
16
2
2019
medline:
18
12
2019
entrez:
16
2
2019
Statut:
ppublish
Résumé
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. 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. 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. Our results provide a preclinical proof of concept for TYRO3 as a potential therapeutic target in bladder cancer.
Sections du résumé
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.
Identifiants
pubmed: 30765874
doi: 10.1038/s41416-019-0397-6
pii: 10.1038/s41416-019-0397-6
pmc: PMC6461973
doi:
Substances chimiques
Proto-Oncogene Proteins
0
MERTK protein, human
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
TYRO3 protein, human
EC 2.7.10.1
c-Mer Tyrosine Kinase
EC 2.7.10.1
Axl Receptor Tyrosine Kinase
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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