Calcium homeostasis modulator GRIN2D activates cancer‐associated fibroblast for desmoplasia and promotes neutrophil infiltration for neutrophil extracellular trap formation in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is recognized as a “cold tumor” due to its poor response to immunotherapy, which is greatly contributed by the dense and complicated tumor microenvironment. Calcium ions (Ca 2+ ) are important signaling molecules for various biological processes. Dysregulated calcium channels and transporters greatly contribute to abnormal calcium homeostasis and, in turn, promote cancer progression. However, its roles in the PDAC tumor microenvironment and therapeutic resistance are still largely unknown. We previously demonstrated the importance of calcium transporters glutamate ionotropic receptor NMDA type subunit 2D (GRIN2D) in promoting PDAC tumor growth and liver metastasis. Here, we studied the importance of GRIN2D in the tumor microenvironment and therapeutic resistance. The upregulated GRIN2D activated cancer-associated fibroblast (CAF) and promoted neutrophil infiltration, contributing to an oncogenic tumor microenvironment. Mechanistically, transcriptome profiling after GRIN2D knockdown in PDAC cells identified fibronectin 1 (FN1) and interleukin-1 beta (IL-1beta) as GRIN2D downstream targets under calcium signaling. The GRIN2D-FN1 pathway activated CAF for tumor desmoplasia, while the GRIN2D-IL-1beta pathway promoted neutrophil infiltration and neutrophil extracellular traps formation. Furthermore, we revealed the epigenetic mechanism leading to the upregulation of GRIN2D in PDAC. We identified a hypermethylated Exon-CpG island at GRIN2D, promoting GRIN2D expression in PDAC tumors. Targeting GRIN2D in the tumor microenvironment enhances the efficacy of both chemotherapies and immunotherapies in inhibiting tumor growth and metastasis. Knowledge gained from this project uncovers the importance of GRIN2D and calcium homeostasis in PDAC progression and contributes to novel therapeutic targets in PDAC.