MassIVE MSV000093747

Partial Public PXD048201

DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer

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Description

Highly malignant pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant immunosuppressive and fibrotic tumor microenvironment (TME). Future therapeutic attempts therefore demand targeting of both compartments in order to be effective. We show here that Dual Specificity and Tyrosine Phosphorylation-regulated Kinase 1B (DYRK1B) represents a compartment-agnostic anti-cancer target in PDAC. DYRK1B is mainly expressed by pancreatic epithelial cancer cells and modulates the influx and activity of TME-associated macrophages through effects on the cancer cells themselves as well as affecting the tumor secretome. Mechanistically, genetic ablation or pharmacological inhibition of DYRK1B strongly attracts tumoricidal macrophages and in addition downregulates the phagocytosis checkpoint and "don't eat me"-signal CD24 on cancer cells, resulting in enhanced tumor cell phagocytosis. Consequently, tumor cells lacking DYRK1B hardly expand in transplantation experiments despite doing so rapidly in culture. Furthermore, combining a small-molecule DYRK1B-directed therapy with mTOR inhibition and conventional chemotherapy stalls the growth of established tumors and results in significant extension of life span in a highly aggressive autochthonous model of PDAC. In light of DYRK inhibitors currently entering clinical phase testing, our data thus provide a novel and clinically translatable approach targeting the cancer cell compartment and its microenvironment, both. [doi:10.25345/C5ZG6GJ46] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: pancreatic ductal adenocarcinoma (PDAC) ; Tyrosine Phosphorylation-regulated Kinase 1B (DYRK1B)

Contact

Principal Investigators:
(in alphabetical order) 		Matthias Lauth, Philipps University Marburg, Germany
Submitting User: graumann

Publications

Brichkina A, Ems M, Suezov R, Singh R, Lutz V, Picard FSR, Nist A, Stiewe T, Graumann J, Daude M, Diederich WE, Finkernagel F, Chung HR, Bartsch DK, Roth K, Keber C, Denkert C, Huber M, Gress TM, Lauth M.
DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer.
Gut. Epub 2024 Jun 4.

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