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Transcriptomic profiling of pancreatic cancer cells and tissues from genetically engineered mouse models

ABSTRACT: This study investigates transcriptomic alterations associated with pancreatic ductal adenocarcinoma (PDAC) progression in genetically engineered mouse models. Total RNA was extracted from two types of samples: (1) pancreatic cancer cells isolated from KPC and KPNiC tumors, and (2) whole pancreatic tissue lysates from WT, NiC, KC, and KNiC mice. RNA-seq libraries were polyA-selected and strand-specific, sequenced on the DNBSEQ-G400 platform (BGI Genomics). Bioinformatic analyses included read alignment (HISAT2), quantification (RSEM), differential gene expression (DESeq2), and gene set enrichment analysis (GSEA). This dataset provides insights into the impact of NIK deletion on pancreatic tumor biology.

ORGANISM(S): Mus musculus

PROVIDER: GSE301904 | GEO | 2026/04/30

REPOSITORIES: GEO

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Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).

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Transcriptomic profiling of pancreatic cancer cells and tissues from genetically engineered mouse models

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