Spatial mosaicism of pancreatic adaptation to ER stress in Ctrb1^Δexon6 mice: implications for human disease

A CTRB2 exon 6 deletion variant is among the top GWAS hits linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC). This variant has been predicted to lead to a truncated CTRB2 protein that misfolds and accumulates in the ER. Using CRISPR/Cas9, we generated a mouse strain carrying the orthologous mutation in Ctrb1 (Ctrb1^Δexon6) and profiled pancreatic tissue over 1.5 years. Ctrb1^Δexon6 mice express a truncated CTRB1 protein that accumulates in the ER, resulting in ER dilation, suppression of the acinar program, and activation of ER stress and inflammatory pathways within three months. With aging, we observed mild histological alterations, reduction of the acinar program, and evidence of adaptive dampening of inflammatory responses, highlighting remarkable long-term organ adaptation to the mutant allele. A key discovery of our study is the mosaic acinar phenotype. Using spatial transcriptomic analysis, we have uncovered discrete acinar cell subpopulations distinguished by the expression of AGR2, one of the most highly upregulated genes in Ctrb1^Δexon6 pancreata. AGR2 is an ER-associated protein disulfide isomerase involved in protein folding. Cells with high amounts of AGR2 displayed higher ER stress signatures and an enrichment of reprogramming (OSKM-associated), underscoring spatially restricted acinar adaptation to chronic ER stress. Inflammatory pathways peaked in cells with high amounts of AGR2 at 3 months. Interestingly, mice harboring the Ctrb1^Δexon6 mutation in heterozygosity displayed an intermediate phenotype. Importantly, human pancreatic tissues from organ donors imputed or genotyped for the deletion variant recapitulated these findings, exhibiting downregulation of the acinar program, upregulation of ER stress pathways, enrichment of the Ctrb1^Δexon6-derived transcriptomic signature, and patchy AGR2 expression. Together, these results demonstrate that spatially heterogeneous acinar remodeling is a central feature of the Ctrb1^Δexon6 phenotype. By linking cell-intrinsic ER stress adaptation to tissue-level mosaicism, our work provides mechanistic insights into how the CTRB2 deletion variant may contribute to PDAC risk.