RACK1 attenuates pancreatic tumorigenesis by suppressing acinar-to-ductal metaplasia through inflammatory signaling modulation

作者：Wei Zhang, Tingting Jiang, Huiqing Zhang, Wei Fang, Xiaojia Li, Keping Xie · 发表于：Cellular Oncology · 年份：2025 · DOI：10.1007/s13402-025-01084-3 · 被引用次数：2 · 研究领域：Pancreatic and Hepatic Oncology Research、NF-κB Signaling Pathways、Pancreatitis Pathology and Treatment

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal malignancies with limited early diagnostic and therapeutic options. Although receptor for activated C kinase 1 (RACK1) is an evolutionarily conserved scaffold protein, its functional role and mechanistic involvement in PDA pathogenesis remain elusive. Using multimodal approaches including: (1) genetically engineered mouse models of pancreatitis and carcinogenesis, (2) patient-derived PDA tissues with matched normal specimens, (3) primary acinar cell 3D cultures, and (4) orthogonal gain/loss-of-function assays in PDA cell lines, we systematically investigated RACK1’s spatiotemporal expression patterns and functional impacts. Mechanistic dissection was performed through gene expression profiling and pathway enrichment analyses with functional validation. RACK1 exhibited progressive silencing across pancreatic lesion progression: acinar cells (normal) > ADM > pancreatic intraepithelial neoplasia (PanIN) > PDA. This acinar-specific protein was undetectable in ductal/islet lineages and was further suppressed under inflammatory challenge. Functionally, RACK1 depletion accelerated ADM initiation and enhanced PDA cell motility and metastatic dissemination in vivo , whereas its overexpression exerted tumor-suppressive effects. Mechanistically, caerulein/TGF-α stimulation and Kras G12D activation converged to inhibit RACK1 while activating MAP2K3-SRC-RELA(p65) signaling nodes, establishing a pro-inflammatory feedforw...