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?-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice.

ABSTRACT: The size of the pancreas is determined by intrinsic factors, such as the number of progenitor cells, and by extrinsic signals that control the fate and proliferation of those progenitors. Both the exocrine and endocrine compartments of the pancreas undergo dramatic expansion after birth and are capable of at least partial regeneration following injury. Whether the expansion of these lineages relies on similar mechanisms is unknown. Although we have shown that the Wnt signaling component ?-catenin is selectively required in mouse embryos for the generation of exocrine acinar cells, this protein has been ascribed various functions in the postnatal pancreas, including proliferation and regeneration of islet as well as acinar cells. To address whether ?-catenin remains important for the maintenance and expansion of mature acinar cells, we have established a system to follow the behavior and fate of ?-catenin-deficient cells during postnatal growth and regeneration in mice. We find that ?-catenin is continuously required for the establishment and maintenance of acinar cell mass, extending from embryonic specification through juvenile and adult self-renewal and regeneration. This requirement is not shared with islet cells, which proliferate and function normally in the absence of ?-catenin. These results make distinct predictions for the relative role of Wnt-?-catenin signaling in the etiology of human endocrine and exocrine disease. We suggest that loss of Wnt-?-catenin activity is unlikely to drive islet dysfunction, as occurs in type 2 diabetes, but that ?-catenin is likely to promote human acinar cell proliferation following injury, and might therefore contribute to the resolution of acute or chronic pancreatitis.

SUBMITTER: Keefe MD

PROVIDER: S-EPMC3380713 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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β-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice.

Keefe Matthew D MD Wang Hui H De La O Jean-Paul JP Khan Ameena A Firpo Matthew A MA Murtaugh L Charles LC

Disease models & mechanisms 20120119 4

The size of the pancreas is determined by intrinsic factors, such as the number of progenitor cells, and by extrinsic signals that control the fate and proliferation of those progenitors. Both the exocrine and endocrine compartments of the pancreas undergo dramatic expansion after birth and are capable of at least partial regeneration following injury. Whether the expansion of these lineages relies on similar mechanisms is unknown. Although we have shown that the Wnt signaling component β-cateni ...[more]

PMID: 22266944

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Project description:Background & aimsIdentification and validation of new functionally relevant and pharmacologically actionable targets for pancreatic ductal adenocarcinoma (PDAC) remains a great challenge. Premalignant acinar cell reprogramming (acinar-to-ductal metaplasia [ADM]) is a precursor of pancreatic intraepithelial neoplasia (PanIN) lesions that can progress to PDAC. This study investigated the role of proline-rich tyrosine kinase 2 (PYK2) in mutant Kras-induced and pancreatitis-associated ADM and PanIN formation, as well as in PDAC maintenance.MethodsGenetically engineered mouse models of mutant Kras (glycine 12 to aspartic acid) and Pyk2 deletion were used for investigating the role of PYK2 in PDAC genesis in mice. In vitro ADM assays were conducted using primary pancreatic acinar cells isolated from mice. Immunohistochemistry, immunofluorescence, and a series of biochemical experiments were used to investigate upstream regulators/downstream targets of PYK2 in pancreatic carcinogenesis. PDAC cell line xenograft experiments were performed to study the role of PYK2 and its downstream target in PDAC maintenance.ResultsPYK2 was increased substantially in ADM lesions induced by mutant Kras or inflammatory injury. Pyk2 deletion remarkably suppressed ADM and PanIN formation in a mutant Kras-driven and pancreatitis-associated PDAC model, whereas PYK2 knockdown substantially inhibited PDAC cell growth in vitro and in nude mice. This study uncovered a novel yes-associated protein 1/transcriptional co-activator with PDZ binding motif/signal transducer and activator of transcription 3/PYK2/β-catenin regulation axis in PDAC. Our results suggest that PYK2 contributes to PDAC genesis and maintenance by activating the Wnt/β-catenin pathway through directly phosphorylating β-cateninY654.ConclusionsThe current study uncovers PYK2 as a novel downstream effector of mutant KRAS signaling, a previously unrecognized mediator of pancreatitis-induced ADM and a novel intervention target for PDAC.

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?-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice.

Publications

β-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice.

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