Glutamate from nerve cells promotes perineural invasion in pancreatic cancer by regulating tumor glycolysis through HK2 mRNA-m6A modification. (January 2023)

• Record Type: Journal Article
• Authors: Li, Fengjiao; He, Chong; Yao, Hanming; Zhao, Yue; Ye, Xijiu; Zhou, Shurui; Zou, Jinmao; Li, Yaqing; Li, Jiajia; Chen, Shaojie; Han, Fanghai; Huang, Kaihong; Lian, Guoda; Chen, Shangxiang
• Is Part Of: Pharmacological research. Volume 187(2023)
• Publication Date: 2023-01
• Subjects: PNI Perineural invasion -- PDAC pancreatic ductal adenocarcinoma -- DRG Matrigel/ dorsal root ganglia -- MR magnetic resonance -- PET-CT positron emission tomography/computed tomography -- ATCC American Type Culture Collection -- FBS fetal bovine serum -- ELISA enzyme-linked immunosorbent assay -- OD optical density -- EMT epithelial-mesenchymal transition -- MS mass spectrometry -- TCGA the Cancer Genome Atlas datasets -- IGF1 Insulin-Like Growth Factor 1 -- TRPV1 Transient Receptor Potential Vanilloid 1 -- ECAR extracellular acidification rate -- KEGG Kyoto Encyclopedia of Genes and Genomes; Pancreatic ductal adenocarcinoma -- Perineural invasion -- Glutamate -- Glycolysis -- N6-methyladenosine; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106555
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Background: Perineural invasion (PNI) has a high incidence and poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Our study aimed to identify the underlying molecular mechanism of PNI and propose effective intervention strategies. Methods: To observe PNI in vitro and in vivo, a Matrigel/ dorsal root ganglia (DRG) model and a murine sciatic nerve invasion model were respectively used. Magnetic resonance (MR) imaging and positron emission tomography/computed tomography (PET-CT) imaging were also used to evaluate tumor growth. Publicly available datasets and PDAC tissues were used to verify how the nerve cells regulate PDAC cells' PNI. Results: Our results showed that glutamate from nerve cells could cause calcium influx in PDAC cells via the N-methyl-d -aspartate receptor (NMDAR), subsequently activating the downstream Ca 2+ dependent protein kinase CaMKII/ERK-MAPK pathway and promoting the mRNA transcription of gene METTL3. Next, METTL3 upregulates the expression of hexokinase 2 (HK2) through N6-methyladenosine (m6A) modification in mRNA, enhances the PDAC cells' glycolysis, and promotes PNI. Furthermore, the IONPs-PEG-scFvCD44v6-scAbNMDAR2B nanoparticles dual targeting CD44 variant isoform 6 (CD44v6) and t NMDAR subunit 2B (NMDAR2B) on PDAC cells were synthesized and verified showing a satisfactory blocking effect on PNI. Conclusions: Here, we firstly provided evidence that glutamate from the nerve cells could upregulate the expression of HK2 through mRNA m6A modification via NMDAR2B and downstream Ca 2+ dependent CaMKII/ERK-MAPK pathway, enhance the glycolysis in PDAC cells, and ultimately promote PNI. In addition, the dual targeting nanoparticles we synthesized were verified to block PNI effectively in PDAC. Graphical Abstract: ga1