Increased Protein Synthesis With Reduced Endoplasmic Reticulum Stress Defines a Specific Adaptation in Pancreatic Acinar Metaplasia

Abstract

Background and 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 physiological conditions, which raises the question of 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.

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 pancreatic ductal adenocarcinoma. We also assessed the level of ribosomal RNA methylation systematically using a deep sequencing–based technique, RiboMethSeq.

Results

During pancreatic tumorigenesis, protein synthesis rates were significantly increased in acinar-to-ductal metaplasia compared with 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 ribosomal RNA methylation at conserved ribosomal positions near the peptidyl transferase center and the exit tunnel, suggesting a potential role in modulating translation and/or cotranslational protein folding. Despite increased protein synthesis, ER stress was reduced, which was associated with an overall reduction in N-linked glycosylation and increased expression of proteasome components.

Conclusion

Our findings reveal a pancreas-specific adaptation of the translational machinery during tumorigenesis, characterized by the production of differentially modified ribosomes and a combination of increased protein synthesis rate and decreased ER stress. This highlights the diversity of adaptive protein synthesis in transforming tissues.