Exploring the role of DYRK1 kinases in cell-autonomous and paracrine activities in pancreatic cancer

Dual-specificity tyrosine-regulated kinases (DYRKs) are a conserved family of protein kinases regulating critical cellular processes. This study investigates the roles of the paralogues DYRK1A and DYRK1B in pancreatic ductal adenocarcinoma (PDAC) cells and their influence on the tumour microenvironment (TME). Transcriptomic analysis of DYRK1A/B-depleted tumour cells revealed their differential roles in cell cycle regulation, extracellular matrix deposition and cytokines/chemokines expression. Loss of DYRK1s in tumour cells reshapes paracrine interactions with cancer-associated fibroblasts and macrophages. Secretome analysis identified soluble factors differentially regulated by DYRK1A/B that contribute to TME reprogramming. Additionally, the characterization of the interaction between DYRK1s and TROAP showed that TROAP acts as a scaffold for DYRK1s and the microtubule-binding protein EB1, facilitating DYRK1A localization at the spindle. DYRK1s phosphorylate TROAP in vitro, and their loss alters TROAP phosphorylation in vivo. Therefore, DYRK1s may influence microtubule dynamics and mitotic progression through TROAP phosphorylation. In summary, this research provides new insights into the multifaceted roles of DYRK1s in PDAC, illustrating their involvement in intrinsic cellular functions and intercellular communication. Targeting DYRK1s may offer therapeutic potential by impairing tumour cell proliferation while modulating the TME to enhance antitumour immune responses.