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Identification of GRIN2D as a novel therapeutic target in pancreatic ductal adenocarcinoma
Jiatong Wang1, Chi Hin Wong1, Yinxin Zhu1
1School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong.
Background:
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a dismal prognosis, and despite significant advances in our understanding of its genetic drivers, like KRAS, TP53, CDKN2A, and SMAD4, effective therapies remain limited. Here, we identified a new therapeutic target GRIN2D and then explored its functions and mechanisms in PDAC progression.
Methods:
We performed a genome-wide RNAi screen in a PDAC xenograft model and identified GRIN2D, which encodes the GluN2D subunit of N-methyl-D-aspartate receptors (NMDARs), as a potential oncogene. Western blot, immunohistochemistry, and analysis on Gene Expression Omnibus were used for detecting the expression of GRIN2D in PDAC. Cellular experiments were conducted for exploring the functions of GRIN2D in vitro while subcutaneous and orthotopic injections were used in in vivo study. To clarify the mechanism, we used RNA sequencing and cellular experiments to identify the related signaling pathway. Cellular assays, RT-qPCR, and western blot helped identify the impacts of the NMDAR antagonist memantine.
Results:
We demonstrated that GRIN2D was highly expressed in PDAC cells, and further promoted oncogenic functions. Mechanistically, transcriptome profiling identified GRIN2D-regulated genes in PDAC cells. We found that GRIN2D promoted PDAC progression by activating the p38 MAPK signaling pathway and transcription factor CREB, which in turn promoted the expression of HMGA2 and IL20RB. The upregulated GRIN2D could effectively promote tumor growth and liver metastasis in PDAC. We also investigated the therapeutic potential of NMDAR antagonism in PDAC and found that memantine reduced the expression of GRIN2D and inhibited PDAC progression.
Conclusion:
Our results suggested that NMDA receptor GRIN2D plays important oncogenic roles in PDAC and represents a novel therapeutic target.
Insights
Researchers identified GRIN2D, a subunit of N-methyl-D-aspartate receptors (NMDARs), as a novel oncogene driving pancreatic cancer progression. Targeting NMDARs with memantine showed therapeutic potential by inhibiting tumor growth and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Neuroscience
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis despite understanding key genetic drivers.
- Effective therapies for PDAC remain limited, necessitating the identification of new therapeutic targets.
Purpose of the Study:
- To identify and investigate GRIN2D as a novel therapeutic target in pancreatic ductal adenocarcinoma.
- To explore the functional roles and underlying mechanisms of GRIN2D in PDAC progression.
Main Methods:
- Genome-wide RNAi screening in PDAC xenograft models to identify potential oncogenes.
- Western blot, immunohistochemistry, and bioinformatics analyses to assess GRIN2D expression.
- In vitro and in vivo cellular and animal studies to evaluate GRIN2D function and therapeutic interventions.
Main Results:
- GRIN2D was found to be highly expressed in PDAC cells, promoting oncogenic functions, tumor growth, and liver metastasis.
- GRIN2D activates the p38 MAPK signaling pathway and CREB, leading to increased HMGA2 and IL20RB expression.
- The N-methyl-D-aspartate receptor (NMDAR) antagonist memantine reduced GRIN2D expression and inhibited PDAC progression.
Conclusions:
- GRIN2D plays a significant oncogenic role in pancreatic ductal adenocarcinoma.
- GRIN2D represents a promising novel therapeutic target for PDAC treatment.
- NMDAR antagonism, exemplified by memantine, offers a potential therapeutic strategy for PDAC.
