DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

Gut. 2019 Aug;68(8):1465-1476. doi: 10.1136/gutjnl-2018-316128. Epub 2018 Oct 20.

Abstract

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.

Keywords: carcinogenesis; cell growth; molecular mechanisms; pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma* / metabolism
  • Adenocarcinoma* / pathology
  • Animals
  • Carcinoma, Pancreatic Ductal* / metabolism
  • Carcinoma, Pancreatic Ductal* / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Dyrk Kinases
  • Fibroblast Growth Factors
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • Pancreatic Neoplasms* / metabolism
  • Pancreatic Neoplasms* / pathology
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins c-met / metabolism*
  • Signal Transduction

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • SPRY2 protein, human
  • Fibroblast Growth Factors
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-met
  • Protein Serine-Threonine Kinases
  • Spry2 protein, mouse