Nuclear GSK-3β and Oncogenic KRas Lead to the Retention of Pancreatic Ductal Progenitor Cells Phenotypically Similar to Those Seen in IPMN

Abstract

Glycogen synthase kinase-3β (GSK-3β) is a downstream target of oncogenic KRas and can accumulate in the nucleus in pancreatic ductal adenocarcinoma (PDA). To determine the interplay between oncogenic KRas and nuclear GSK-3β in PDA development, we generated Lox-STOP-Lox (LSL) nuclear-targeted GSK-3β animals and crossed them with LSL-KRasG12D mice under the control of the Pdx1-cre transgene—referred to as KNGC. Interestingly, 4-week-old KNGC animals show a profound loss of acinar cells, the expansion of ductal cells, and the rapid development of cystic-like lesions reminiscent of intraductal papillary mucinous neoplasm (IPMN). RNA-sequencing identified the expression of several ductal cell lineage genes including AQP5. Significantly, the Aqp5+ ductal cell pool was proliferative, phenotypically distinct from quiescent pancreatic ductal cells, and deletion of AQP5 limited expansion of the ductal pool. Aqp5 is also highly expressed in human IPMN along with GSK-3β highlighting the putative role of Aqp5+ ductal cells in human preneoplastic lesion development. Altogether, these data identify nGSK-3β and KRasG12D as an important signaling node promoting the retention of pancreatic ductal progenitor cells, which could be used to further characterize pancreatic ductal development as well as lineage biomarkers related to IPMN and PDA.

Metabolic Reprogramming by Mutant GNAS Creates an Actionable Dependency in Intraductal Papillary Mucinous Neoplasms of the Pancreas

“…Tff2), it can also be an initial step towards dysplasia and tumorigenesis [9, 10]. Interestingly, analogous gastric pit and SPEM markers are also characteristic of low grade (gastric) IPMNs, which are the most common subtype of IPMNs [23, 24, 25]. Our findings demonstrate that mutant GNAS at least partially contributes to the gastric metaplastic phenotype characteristic of low-grade IPMNs.…”

Oncogenic GNAS drives a gastric pylorus program in intraductal papillary mucinous neoplasms of the pancreas

“…We are hard pressed to understand what drives cyst formation in these cases, though our data suggest that KRAS is sufficient and that these IPMN may be MUCL3-negative. Studies in mice have suggested the formation of IPMN-like, AQP5+ lesions driven be oncogenic KRAS and nuclear expression of GSK3β 51 . Further, a recent study shows that loss of RNF43 expression in the context of oncogenic KRAS expression is sufficient to drive IPMN/cyst formation and accelerated tumorigenesis in mice 52 .…”

“…lesions driven be oncogenic KRAS and nuclear expression of GSK3b 51 . Further, a recent study shows that loss of RNF43 expression in the context of oncogenic KRAS expression is sufficient to drive IPMN/cyst formation and accelerated tumorigenesis in mice 52 .…”

Modern aspects of the management of pancreatic intraductal papillary mucinous neoplasms: a narrative review

“…In IPMNs with high-grade dysplasia, a relative depletion of T-cells with enriched macrophages is present compared to low-grade dysplasia [ 73 , 74 ]. Glycogen synthase kinase-3beta (GSK-3β) and KRASG12D promote the retention of pancreatic ductal progenitor cells and are new lineage biomarkers related to IPMN and pancreatic cancer [ 75 ]. In current clinical practice, none of the known biomarkers allow for the selection of candidates for surgery, observation, or neither [ 76 ].…”

“…Glycogen synthase kinase-3beta (GSK-3β) and KRAS G12D promote the retention of pancreatic ductal progenitor cells and are new lineage biomarkers related to IPMN and pancreatic cancer [75].…”