Differences in the Degree of Cerulein-Induced Chronic Pancreatitis in C57BL/6 Mouse Substrains Lead to New Insights in Identification of Potential Risk Factors in the Development of Chronic Pancreatitis

Ulmasov, Barbara; Oshima, Kiyoko; Rodríguez, Mauricio; Cox, Roger D.; Neuschwander‐Tetri, Brent A.

doi:10.1016/j.ajpath.2013.05.020

Cited by 62 publications

(49 citation statements)

References 56 publications

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“…To find molecular regulators of this process, we performed gene set enrichment analysis 26 on the published transcriptional profile of mouse pancreata treated with caerulein 22 to identify pathways up-regulated in pancreatitis (Supplementary Figure 1 A ). Many of these pathways, such as Wnt, Notch, and JAK–STAT3, have previously been implicated in either acinar cell regeneration or in inducing ADM upon injury 13, 27, 28, 29.…”

Section: Resultsmentioning

confidence: 99%

YAP1 and TAZ Control Pancreatic Cancer Initiation in Mice by Direct Up-regulation of JAK–STAT3 Signaling

et al. 2016

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Background & AimsPancreatitis is the most important risk factor for pancreatic ductal adenocarcinoma (PDAC). Pancreatitis predisposes to PDAC because it induces a process of acinar cell reprogramming known as acinar-to-ductal metaplasia (ADM)—a precursor of pancreatic intraepithelial neoplasia lesions that can progress to PDAC. Mutations in KRAS are found at the earliest stages of pancreatic tumorigenesis, and it appears to be a gatekeeper to cancer progression. We investigated how mutations in KRAS cooperate with pancreatitis to promote pancreatic cancer progression in mice.MethodsWe generated mice carrying conditional alleles of Yap1 and Taz and disrupted Yap1 and Taz using a Cre-lox recombination strategy in adult mouse pancreatic acinar cells (Yap1fl/fl;Tazfl/fl;Ela1-CreERT2). We crossed these mice with LSL-KrasG12D mice, which express a constitutively active form of KRAS after Cre recombination. Pancreatic tumor initiation and progression were analyzed after chemically induced pancreatitis. We analyzed pancreatic tissues from patients with pancreatitis or PDAC by immunohistochemistry.ResultsOncogenic activation of KRAS in normal, untransformed acinar cells in the pancreatic tissues of mice resulted in increased levels of pancreatitis-induced ADM. Expression of the constitutive active form of KRAS in this system led to activation of the transcriptional regulators YAP1 and TAZ; their function was required for pancreatitis-induced ADM in mice. The JAK–STAT3 pathway was a downstream effector of KRAS signaling via YAP1 and TAZ. YAP1 and TAZ directly mediated transcriptional activation of several genes in the JAK–STAT3 signaling pathway; this could be a mechanism by which acinar cells that express activated KRAS become susceptible to inflammation.ConclusionsWe identified a mechanism by which oncogenic KRAS facilitates ADM and thereby generates the cells that initiate neoplastic progression. This process involves activation of YAP1 and TAZ in acinar cells, which up-regulate JAK–STAT3 signaling to promote development of PDAC in mice.

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Section: Resultsmentioning

confidence: 99%

YAP1 and TAZ Control Pancreatic Cancer Initiation in Mice by Direct Up-regulation of JAK–STAT3 Signaling

et al. 2016

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“…C57BL/6 is the most frequently used mouse strain for this type of biomedical research (Ulmasov et al, 2013). Fibrosis may be reversible only in its early stages.…”

Section: Methodsmentioning

confidence: 99%

Essential Role of Lyn in Fibrosis

et al. 2016

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Fibrotic disorders involve replacement of normal parenchyma with myofibroblasts, which deposit connective tissue, leading to obliteration of the function of the underlying organ. The treatment options are inadequate and reflect the fact that signaling targets in myofibroblasts are unknown. Here we identify the hyperactive Lyn signaling in myofibroblasts of patients with chronic pancreatitis-induced fibrosis. Lyn activation coexpress with markers of activated myofibroblasts, and is increased ~11-fold in chronic pancreatitis compared to normal tissue. Inhibition of Lyn with siRNA or INNO-406 leads to the substantial decrease of migration and proliferation of human chronic pancreatitis myofibroblasts in vitro, while leaving migration and proliferation of normal myofibroblasts only slightly affected. Furthermore, inhibition of Lyn prevents synthesis of procollagen and collagen in myofibroblasts in a mouse model of chronic pancreatitis-induced fibrosis. We conclude that Lyn, as a positive regulator of myofibroblast migration, proliferation, and collagen production, is a key target for preventing fibrosis.

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“…For example, the time course of zymogen activation, the degree of inflammation, and the pattern of cell death are distinct. Furthermore, the ability of repeated doses of cerulein to cause fibrosis in a chronic pancreatitis model depends on the mouse strain 24 . We believe that the cerulein model likely is relevant to initiator mechanisms in acute clinical pancreatitis, at least those that follow the earliest factors such as acinar cell–receptor activation.…”

Section: Animal Models Of Clinical Acute Pancreatitismentioning

confidence: 98%

Do Animal Models of Acute Pancreatitis Reproduce Human Disease?

Gorelick

Lerch

2017

Cellular and Molecular Gastroenterology and Hepatology

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Acute pancreatitis is currently the most common cause of hospital admission among all nonmalignant gastrointestinal diseases. To understand the pathophysiology of the disease and as a potential step toward developing targeted therapies, attempts to induce the disease experimentally began more than 100 years ago. Recent decades have seen progress in developing new experimental pancreatitis models as well as elucidating many underlying cell biological and pathophysiological disease mechanisms. Some models have been developed to reflect specific causes of acute pancreatitis in human beings. However, the paucity of data relating to the molecular mechanisms of human disease, the likelihood that multiple genetic and environmental factors affect the risk of disease development and its severity, and the limited information regarding the natural history of disease in human beings make it difficult to evaluate the value of disease models. Here, we provide an overview of key models and discuss our views on their strengths for characterizing cell biological disease mechanisms or for identifying potential therapeutic targets. We also acknowledge their limitations.

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Differences in the Degree of Cerulein-Induced Chronic Pancreatitis in C57BL/6 Mouse Substrains Lead to New Insights in Identification of Potential Risk Factors in the Development of Chronic Pancreatitis

Cited by 62 publications

References 56 publications

YAP1 and TAZ Control Pancreatic Cancer Initiation in Mice by Direct Up-regulation of JAK–STAT3 Signaling

YAP1 and TAZ Control Pancreatic Cancer Initiation in Mice by Direct Up-regulation of JAK–STAT3 Signaling

Essential Role of Lyn in Fibrosis

Do Animal Models of Acute Pancreatitis Reproduce Human Disease?

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