Unexpected combination of increased protein translation and decreased endoplasmic reticulum stress during pancreatic cancer initiation

Background & Aims: Tumorigenesis is usually associated with increased protein synthesis rates coupled with increased endoplasmic reticulum (ER) stress. In the pancreas, acinar cells already exhibit a very high protein synthesis rate in normal condition, which raises the question as to how this cell type adapts during pancreatic tumor formation. Here, we characterize how acinar cells modulate their protein synthesis rate in metaplastic lesions, which are precursor lesions of pancreatic ductal adenocarcinoma (PDAC). Methods: We evaluated protein synthesis by puromycin incorporation assays and investigated the control of translation and ER stress by transcriptomic analyses and phenotyping of a mouse model of PDAC. We also assessed the level of ribosomal RNA (rRNA) methylation systematically using a deep-sequencing-based technique, RiboMethSeq. Results: During pancreatic tumorigenesis, protein synthesis levels in acinar-to-ductal metaplasia exhibited a significant increase as compared to normal acinar cells. This was associated with enhanced expression and activity of translation initiation factors, and with increased production of ribosomal components and ribosome assembly factors. We detected differential rRNA methylation at conserved ribosomal positions near the peptidyl-transferase center and the exit tunnel, suggesting a possible role in modulating translation and/or initial protein folding. Despite increased protein synthesis, ER stress was reduced, which was associated with an overall reduction in N-glycosylation and increased expression of proteasome components. Conclusions: Our work provides evidence for a pancreas-specific adaptation of the translation program during tumorigenesis, characterized by the production of differentially modified ribosomes and a rather unexpected combination of increased protein synthesis rate and decreased ER stress. This highlights the diversity of adaptive protein translation in transforming tissues. RiboMethSeq sequencing data from "Ela-K" and "Ela-K+cerulein" samples that refer to Fig.4 A and B