Acinar-to-ductal metaplasia (ADM) is a recently recognized, yet less well-studied, precursor lesion of pancreatic ductal adenocarcinoma (PDAC) developed in the setting of chronic pancreatitis. Through digital spatial mRNA profiling, we compared ADM and adjacent PDAC tissues from patient samples to unveil the bridging genes during the malignant transformation of pancreatitis. By comparing the bridging genes with the 7-methylguanosine (m7G)-seq dataset, we screened 19 m7G methylation genes for a subsequent large sample analysis. We constructed the “m7G score” model based on the RNA-seq data for pancreatic cancer in The Cancer Genome Atlas (TCGA) database and The Gene Expression Omnibus (GEO) database. Tumors with a high m7G score were characterized by increased immune cell infiltration, increased genomic instability, higher response rate to combined immune checkpoint inhibitors (ICIs), and overall poor survival. These findings indicate that the m7G score is associated with tumor invasiveness, immune cell infiltration, ICI treatment response, and overall patients’ survival. We also identified FN1 and ITGB1 as core genes in the m7Gscore model, which affect immune cell infiltration and genomic instability not only in pancreatic cancer but also in pan-cancer. FN1 and ITGB1 can inhibit immune T cell activition by upregulation of macrophages and neutrophils, thereby leading to immune escape of pancreatic cancer cells and reducing the response rate of ICI treatment.

Persistent acinar to ductal metaplasia (ADM) is a recently recognized precursor of pancreatic ductal adenocarcinoma (PDAC). Here we show that the ADM area of human pancreas tissue adjacent to PDAC expresses significantly higher levels of regenerating protein 3A (REG3A). Exogenous REG3A and its mouse homolog REG3B induce ADM in the 3D culture of primary human and murine acinar cells, respectively. Both Reg3b transgenic mice and REG3B-treated mice with caerulein-induced pancreatitis develop and sustain ADM. Two out of five Reg3b transgenic mice with caerulein-induced pancreatitis show progression from ADM to pancreatic intraepithelial neoplasia (PanIN). Both in vitro and in vivo ADM models demonstrate activation of the RAS-RAF-MEK-ERK signaling pathway. Exostosin-like glycosyltransferase 3 (EXTL3) functions as the receptor for REG3B and mediates the activation of downstream signaling proteins. Our data indicates that REG3A/REG3B promotes persistent ADM through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway. Targeting REG3A/REG3B, its receptor EXTL3, or other downstream molecules could interrupt the ADM process and prevent early PDAC carcinogenesis.

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