RBPJ deficiency sensitizes pancreatic acinar cells to Kras-mediated PanIN initiation

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is among the most common causes of cancer death worldwide. KrasG12D mutation is the main driver mutation but insuffi-cient for progression of invasive cancer on its own indicating that other pathways, such as Notch signaling may participate in that process. RBPJ, the only transcription factor in Notch signaling, is frequently lost in human cancers and associated with more aggressive breast cancer phenotype. Notch-independently, in complex with P48, RBPJ initiates transcription of its paralogue RBPJL ensuring acinar differentiation. The RBPJ knockout has an embryonic lethal effect. Mice with pancreas-specific deletion of RBPJ presented with less acinar tissue and large duct-like structures suggesting a relevance of RBPJ for acinar to ductal reprogramming and even pancreatic neoplasia. Here, we found reduced RBPJ expression level in the human PDAC specimens. Analyses of transgenic mouse models of an inducible P48-dependent RBPJ knockout revealed that it is dispensable for the maintenance adult acinar cells. In the context of oncogenic KRAS expression, the RBPJ deficiency facilitated the development of PanIN lesions with massive fibrotic stroma. Interestingly, RNA seq data revealed corresponding transcription pattern prior to phenotypic alterations. RNA-seq was performed by whole RNA islation from pancreata harvested from 4 weeks after oil/tamoxifen treated 6-8 weeks old iCR (P48-CreERT;Rbpjflox/flox), iKC (P48-CreERT; LSL-KrasG12D), and iKCR (P48-CreERT; LSL-KrasG12D ;Rbpjflox/flox) mice (n=6/group).