2024-11-05
The role of macrophages in pancreatic cancer: A new resistance mechanism revealed?
Oncology
This study was initiated to characterize the mechanisms by which macrophages could be transformed into antitumor allies in pancreatic cancer. In particular, attention was given to DYRK1B kinase, an enzyme in pancreatic cancer cells, whose inhibition may alter macrophage behavior, steering them toward a tumoricidal action.
Role of DYRK1B in controlling macrophages
In this study, researchers used murine PDAC models and human cell lines to evaluate the impact of DYRK1B inhibition on macrophage activity. Murine pancreatic cancer cells (mKpc4) with genetic ablation of Dyrk1b (KO) were generated and transplanted alongside control cells. To analyze changes within the tumor microenvironment (TME), RNA sequencing and immunofluorescence techniques were applied to the tumors. Finally, they studied how DYRK1B inhibition influences the macrophages' capacity to phagocytize tumor cells.
The main findings of this study are as follows:
- DYRK1B ablation results in slower tumor growth in vivo in mice, despite increased proliferation in vitro.
- DYRK1B KO tumors exhibit a significant accumulation of macrophages with an M1 polarization profile (pro-inflammatory and tumoricidal), enhancing their antitumor potential.
- DYRK1B inhibition led to increased CD24 expression on the surface of tumor cells, thereby limiting phagocytosis by macrophages.
- The inhibition of DYRK1B, combined with mTOR-targeted therapies and chemotherapy, significantly extends survival in aggressive pancreatic cancer models.
DYRK1B: a promising therapeutic target in pancreatic cancer treatment
This study suggests that DYRK1B plays a key role in modulating the TME in pancreatic cancer. By promoting macrophage suppression and shielding tumor cells from phagocytosis, DYRK1B actively contributes to treatment resistance. Inhibiting DYRK1B thus opens promising avenues to leverage the immune potential of macrophages in PDAC, particularly by reprogramming these cells toward an active response against tumors. These findings encourage further research on molecular inhibitors of DYRK1B, currently in clinical trials. This approach could improve PDAC treatment by enhancing innate immunity, making therapies more effective against this challenging cancer.
Source(s) :
Brichkina, A., et al. (2024). DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer. Gut. ;
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