Identification of GRIN2D as a novel therapeutic target in pancreatic ductal adenocarcinoma

Jiatong Wang; Chi Hin Wong; Yinxin Zhu; Xiaoqiang Yao; Kelvin K C Ng; Chengzhi Zhou; Ka Fai To; Yangchao Chen

doi:10.1186/s40364-023-00514-4

Identification of GRIN2D as a novel therapeutic target in pancreatic ductal adenocarcinoma

Biomark Res. 2023 Aug 8;11(1):74. doi: 10.1186/s40364-023-00514-4.

Authors

Jiatong Wang¹, Chi Hin Wong¹, Yinxin Zhu¹, Xiaoqiang Yao¹, Kelvin K C Ng², Chengzhi Zhou³, Ka Fai To⁴, Yangchao Chen^{5

6}

Affiliations

¹ School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong.
² Department of Surgery, The Chinese University of Hong Kong, Shatin NT, Hong Kong.
³ State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁴ Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.
⁵ School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin NT, Hong Kong. yangchaochen@cuhk.edu.hk.
⁶ Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. yangchaochen@cuhk.edu.hk.

Abstract

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.

Keywords: GRIN2D; NMDA receptor; Oncogene; Pancreatic ductal adenocarcinoma; Therapeutic target.

Abstract

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