A Common CTRB misfolding variant associated with pancreatic cancer risk causes ER stress and inflammation in mice

Background Genome-wide association studies have identified an exon 6 CTRB2 deletion variant proposed to increase pancreatic cancer risk. Objective To acquire evidence on its causal role, we developed and analysed a new mouse strain carrying an equivalent variant in Ctrb1 , the mouse CTRB2 orthologue. Design We used CRISPR/Cas9 to introduce a 707 bp deletion encompassing Ctrb1 exon 6 ( Ctrb1 Δexon6 ). This mutation closely mimics the human variant. Mice carrying the mutant allele were profiled at 3 months to assess their phenotype. Results Ctrb1 Δexon6 mutant mice express a truncated CTRB1 that accumulates in the endoplasmic reticulum (ER). The pancreas of homozygous mutant mice displays reduced chymotrypsin activity, total protein synthesis and amylase secretion. The histological aspect of the pancreas is inconspicuous but ultrastructural analysis shows evidence of dramatic ER stress and cytoplasmic and nuclear inclusions. Transcriptomic studies of the mutant pancreas reveal downregulation of the acinar programme and increased activity of ER stress-related and inflammatory pathways. Agr2 is one of the most upregulated genes in mutant pancreata. Heterozygous mice have an intermediate phenotype. Ctrb1 Δexon6 mutant mice exhibit impaired recovery from acute caerulein-induced pancreatitis. Administration of tauroursodeoxycholic acid or sulindac partially alleviates the phenotype. A transcriptomic signature derived from the mutant pancreata is significantly enriched in normal human pancreas of CTRB2 exon 6 deletion variant carriers from the GTEx cohort. Conclusions This mouse strain provides evidence that the exon 6 deletion causes ER stress and inflammation and is an excellent model to understand its contribution to pancreatic cancer and identify preventive strategies.