胰导管腺癌（PDAC）是一种预后差劲的毁灭性疾病，尽管我们对其遗传驱动因子（如KRAS、TP53、CDKN2A和SMAD4）的理解取得了显著进展，但有效的治疗方法仍然有限。在这里，我们鉴定了一个新的治疗靶点GRIN2D，并探索了其在PDAC进展中的功能和机制。我们在PDAC异种移植模型中进行了全基因组RNAi筛选，并发现了编码N-甲基-D-天冬氨酸受体（NMDARs）GluN2D亚单位的GRIN2D作为一个潜在的癌基因。通过Western blot、免疫组化和基因表达数据库分析，检测了PDAC中GRIN2D的表达。进行了细胞实验以探索GRIN2D在体外的功能，而亚皮下和原位注射则用于体内实验。为了阐明机制，我们使用RNA测序和细胞实验来鉴定相关的信号通路。利用细胞实验、RT-qPCR和Western blot鉴定NMDAR拮抗剂膜内嘧啶的影响。我们证明了GRIN2D在PDAC细胞中高表达，并进一步促进了癌基因的功能。在机制上，转录组谱定鉴定了PDAC细胞中GRIN2D调控的基因。我们发现GRIN2D通过激活p38 MAPK信号通路和转录因子CREB来促进PDAC进展，从而促进HMGA2和IL20RB的表达。上调的GRIN2D能够有效促进PDAC肿瘤的生长和肝转移。我们还研究了NMDAR拮抗在PDAC中的治疗潜力，并发现膜内嘧啶可以降低GRIN2D的表达并抑制PDAC进展。我们的结果表明，NMDA受体GRIN2D在PDAC中具有重要的癌基因作用，并且是一个新的治疗靶点。© 2023. Yumed Inc. 和BioMed Central Ltd.，Spinger Nature的一部分。

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.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.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.Our results suggested that NMDA receptor GRIN2D plays important oncogenic roles in PDAC and represents a novel therapeutic target.© 2023. Yumed Inc. and BioMed Central Ltd., part of Springer Nature.