Background and aims Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumour with a poor prognosis using current treatments. Targeted therapies may offer a new avenue for more effective strategies. Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase with contradictory roles in different tumours that is uncharacterised in PDAC. Here, we aimed to investigate the role of DYRK1A in pancreatic tumorigenesis.
Design We analysed DYRK1A expression in PDAC genetic mouse models and in patient samples. DYRK1A function was assessed with knockdown experiments in pancreatic tumour cell lines and in PDAC mouse models with genetic reduction of Dyrk1a dosage. Furthermore, we explored a mechanistic model for DYRK1A activity.
Results We showed that DYRK1A was highly expressed in PDAC, and that its protein level positively correlated with that of c-MET. Inhibition of DYRK1A reduced tumour progression by limiting tumour cell proliferation. DYRK1A stabilised the c-MET receptor through SPRY2, leading to prolonged activation of extracellular signal-regulated kinase signalling.
Conclusions These findings reveal that DYRK1A contributes to tumour growth in PDAC, at least through regulation of c-MET accumulation, suggesting that inhibition of DYRK1A could represent a novel therapeutic target for PDAC.
- pancreatic cancer
- cell growth
- molecular mechanisms
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SL and CF share senior authorship.
JL and JB contributed equally.
Contributors JL and JB designed and performed the experiments, analysed the data and gave input to the manuscript; MC analysed human histological samples; XB-DR performed computational analysis; EN-M performed experiments; MG provided RNA samples of patients with PDAC; ECV and MLA provided KPC and Dyrk1a +/- mice; SdlL and CF devised the project, coordinated the work, analysed data and wrote the manuscript. All authors approved the manuscript.
Funding This work was supported by grants from the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) (BIO2014-57716-C2-2-R, BIO2017-89754-C2-2R to CF and BFU2016-76141-P to SL), and receives partial support from the Generalitat de Catalunya (SGR14/248 to CF and SGR14/674 to SL). CIBER de Enfermedades Raras and de Enfermedades Hepáticas y Digestivas are initiatives of the Instituto de Salud Carlos III (ISCIII). The group of CF is partially financed by the ISCIII (IIS10/00014), co-financed by Fondo Europeo de Desarrollo Regional (FEDER), and acknowledges the support of the COST Action BM1204 EUPancreas. MG acknowledges grant PI17/01003 from ISCIII.
Competing interests None declared.
Patient consent Not required.
Ethics approval The study was approved by the HCB Institutional Ethics Committee. All animal procedures met the guidelines of European Community Directive 86/609/EEC and were approved by the Ethical Committee (CEEA-University of Barcelona) and by the local authorities (Generalitat de Catalunya).
Provenance and peer review Not commissioned; externally peer reviewed.
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