β-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice

Abstract

Cellular plasticity in adult organs is involved in both regeneration and carcinogenesis. WT mouse acinar cells rapidly regenerate following injury that mimics acute pancreatitis, a process characterized by transient reactivation of pathways involved in embryonic pancreatic development. In contrast, such injury promotes the development of pancreatic ductal adenocarcinoma (PDA) precursor lesions in mice expressing a constitutively active form of the GTPase, Kras, in the exocrine pancreas. The molecular environment that mediates acinar regeneration versus the development of PDA precursor lesions is poorly understood. Here, we used genetically engineered mice to demonstrate that mutant Kras promotes acinar-to-ductal metaplasia (ADM) and pancreatic cancer precursor lesion formation by blocking acinar regeneration following acute pancreatitis. Our results indicate that β-catenin is required for efficient acinar regeneration. In addition, canonical β-catenin signaling, a pathway known to regulate embryonic acinar development, is activated following acute pancreatitis. This regeneration-associated activation of β-catenin signaling was not observed during the initiation of Kras-induced acinar-to-ductal reprogramming. Furthermore, stabilized β-catenin signaling antagonized the ability of Kras to reprogram acini into PDA preneoplastic precursors. Therefore, these results suggest that β-catenin signaling is a critical determinant of acinar plasticity and that it is inhibited during Kras-induced fate decisions that specify PDA precursors, highlighting the importance of temporal regulation of embryonic signaling pathways in the development of neoplastic cell fates. IntroductionPancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States (1). Analysis of patient samples and genetically engineered mouse models suggests that it likely develops from preneoplastic ductal lesions, including pancreatic intraepithelial neoplasias (PanINs) (2). Understanding how signaling pathways interact in the pancreatic epithelium to elicit PanINs therefore represents a key step in the possible development of tools for early PDA detection and treatment. While PanINs express markers of ductal differentiation, many recent studies suggest that they can arise from pancreatic acinar cells that are reprogrammed into a preneoplastic state by undergoing acinar-toductal metaplasia (ADM) (3-7).Activating mutations in the gene encoding the GTPase Kras are nearly universal in human PDA (8), and targeting of mutated Kras to mouse pancreatic progenitors recapitulates the human PanIN-to-PDA progression sequence (9). While ADM is observed in these models (6) and Kras can spontaneously induce ADM and PanIN formation when activated in adult acini (3, 4, 7), expression of mutant Kras in acinar cells does not guarantee ductal reprogramming. Acini expressing mutant Kras during embryogenesis appear grossly unaffected (9), and some normal acinar tissue is maintained in the context of PanIN and PDA progression as mice age (9, 10...

Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment

“…In Kras-driven mouse models of PDAC, acute and chronic pancreatitis markedly accelerates pancreatic intraepithelial neoplasia (PanIN) and PDAC development (10,11). These data illustrate the contribution of chronic inflammation to pancreatic carcinogenesis.…”

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

“…As professional secretory cells, acinar cells are highly dependent on ER functions and are particularly susceptible to ER stress (40). Interestingly, acinar cells respond to stress such as pancreatitis through activation of regenerative mechanisms that initiate ADM, a process that replaces damaged acinar cells with duct-like structures (41). Although the relationship between ER stress and ADM is not well understood, a recent report suggests that ER stress resulting from perturbation of basal autophagy via loss of ATG7 is associated with spontaneous activation of ADM in a mouse model (42).…”

Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation

“…5) suggest that aberrant expression of LRH-1 might be linked to proliferation of dedifferentiated pancreatic cancer cells, which are associated with aggressive pancreatic tumors (37). Recent studies demonstrated the inherent plasticity of pancreatic cells that can be reprogrammed to the transient dedifferentiated progenitor-like states, which can give rise to PDAC (38)(39)(40). Because of the established roles of LRH-1 in pancreatic and stem cell differentiation (7-9, 20), we hypothesize that this receptor might contribute to the reprogramming events in the adult pancreas that lead to its transformation.…”