CRUCIAL ROLE OF SECRETORY ORGANELLE DYNAMICS IN PANCREATIC ACINAR CELL RESPONSE TO INJURY, METAPLASIA, AND TUMORIGENESIS

In the pancreas, repeated acute pancreatitis and chronic pancreatitis cause an increased risk of progression to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) via a metaplastic event in the secretory acinar cell known as acinar-to-ductal metaplasia (ADM). ADM proceeds through an evolutionarily conserved cell program called paligenosis, a three-step process (autophagy, metaplastic gene expression, and proliferation) that terminally differentiated cells use to re-enter the cell cycle.
Little is known about the precise changes that occur in this crucial secretory translation axis during paligenosis and how this process is involved in tumorigenesis in pancreatic acinar cells. Our work here will show that one of the most obvious changes that occur during paligenosis is in the organelles required for secretion, in particular the ribosomes associated with the rough endoplasmic reticulum (rER).
We observed that during the initial catabolic phase of paligenosis, an almost simultaneous reduction in the amount of ribosomal small and large subunits and the amount of ER was noted, which occurs through both autophagy and the ubiquitin-proteasome system. We also found that the functional and structural remodeling of ribosomes and the ER occurred through two injury-responsive, ribosome-related proteins, IFRD1 and ZFP36L1. An 80S-assembled ribosome-binding protein, IFRD1, also known as TIS7, increased and specifically inhibited the translation of the ribosome it was bound to, thereby serving as a ‘brake’ on ER translation. Next, ZFP36L1, also known as TIS11B, accumulated near the ER, serving as a haven to protect ribosomes and mRNAs, in particular AU-rich cytosolic transcripts, required for anabolic growth.
Next, we showed that those ribosome salvaging mechanisms collaborate with ribosome biogenesis in the later, anabolic stage of paligenosis. Loss of Nat10, which we show is required for ribosome biogenesis, blocked both progression through the cell cycle and post-injury restoration of secretory cell architecture. The Nat10Δ/Δ phenotype was ameliorated when we also deleted the tumor suppressor p53, indicating ribosome biogenesis is a cell proliferation licensing step for paligenosis.
Finally, we showed that loss of paligenotic regulation of the dynamic ribosome changes we have observed blocks not just paligenosis but also prevents the progression of cancer at the pre-cancerous stages: deletion of Nat10 blocks development of PanIN lesions in the Kras G12D mutant mouse model of PDAC tumorigenesis.
These findings provide important answers and further understanding of how paligenosis, specifically dynamic regulation of ribosomes, works within acinar cells to fuel PanIN and PDAC, suggesting drugs that target ribosomes might eventually add to our anti-cancer arsenal.