Citations

AbstractAcinar‐to‐ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre‐malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase‐3beta (GSK‐3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK‐3β promotes TGF‐α‐induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK‐3β attenuates caerulein‐induced ADM formation and PanIN progression in KrasG12D transgenic mice. Furthermore, we demonstrate that GSK‐3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas‐driven cell proliferation. Mechanistically, we show that GSK‐3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK‐3β participates in early pancreatitis‐induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Abstract Pancreatic cancer is characterized by an inflammatory environment. Here we delineate the crosstalk between different macrophage populations with pancreatic cells carrying oncogenic Kras mutations. First, we show that pancreatic acinar cells that undergo oncogenic transformation by mutant Kras upregulate chemoattractants that attract inflammatory macrophages. These inflammatory macrophages contribute to acinar cell dedifferentiation to a progenitor-like cell type (acinar-to-ductal metaplasia; ADM). Resulting cells can give rise to PanIN lesions. We then provide insight at which stage of PanIN formation a switch between inflammatory and alternatively-activated macrophages occurs; and define one mechanism by which this can be mediated. Eventually, we provide insight of how alternatively-activated macrophages facilitate the further progression of PanIN lesions to a more aggressive phenotype. Citation Format: Geou-Yarh Liou, Heike Doeppler, Ligia Bastea, Peter Storz.{Authors}. Crosstalk of different macrophage populations with pancreatic acinar or PanIN cells and contribution to development of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A59.

Abstract The development of pancreatic cancer requires both obtain of oncogenic Kras mutations and up-regulation of growth factor signaling. However, how oncogenic Kras regulates growth factor signaling in pancreatic cancer development is still unclear. Using a transgenic mouse model harboring an oncogenic Kras mutation and a 3D organoid explant culture of primary pancreatic acini, we here show that expression of mutant Kras in pancreatic acinar cells alters their mitochondrial metabolism, resulting in increased generation of mitochondrial reactive oxygen species (mROS). We further demonstrate that mROS induced by oncogenic Kras is required for transdifferentiating acinar cells to a duct-like phenotype and eventually progression to pancreatic intraepithelial neoplasia (PanIN), the most common precursor lesions of pancreatic ductal adenocarcinoma (PDAC). This transdiffentiation process is mediated by increased levels of epidermal growth factor receptor (EGFR) as well as its ligands, EGF and TGFα, through activation of the ROS-receptive transcription factors, NF-κB1 and NF-κB2. In Kas transgenic mice, the interception of KrasG12D-mediated generation of mROS significantly reduced the formation of pre-neoplastic lesions. Hence, our data provide mechanistic insight of how oncogenic Kras mutant crosstalks with growth factor signaling to cause the formation of pancreatic cancer. Citation Format: Geou-Yarh Liou, Heike Doeppler, Kathleen E. DelGirono, Howard C. Crawford, Michael P. Murphy, Peter Storz. Oncogenic Kras-induced mitochondrial oxidative stress in pancreatic acini modulates the formation of precancerous lesions through autocrine EGFR signaling. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr PR01.

Abstract Desmoplasia and an inflammatory environment are defining features of pancreatic cancer. Unclear is how pancreatic cells that undergo oncogenic transformation can cross-talk with immune cells and how this contributes to the development of pancreatic lesions. Here, we demonstrate that pancreatic acinar cells expressing mutant KRAS can expedite their transformation to a duct-like phenotype by inducing local inflammation. Specifically, we show that KRASG12D induces the expression of intercellular adhesion molecule-1 (ICAM-1), which serves as chemoattractant for macrophages. Infiltrating macrophages amplify the formation of KRASG12D-caused abnormal pancreatic structures by remodeling the extracellular matrix and providing cytokines such as TNF. Depletion of macrophages or treatment with a neutralizing antibody for ICAM-1 in mice expressing oncogenic Kras under an acinar cell–specific promoter resulted in both a decreased formation of abnormal structures and decreased progression of acinar-to-ductal metaplasia to pancreatic intraepithelial neoplastic lesions. Significance: We here show that oncogenic KRAS in pancreatic acinar cells upregulates the expression of ICAM-1 to attract macrophages. Hence, our results reveal a direct cooperative mechanism between oncogenic Kras mutations and the inflammatory environment to drive the initiation of pancreatic cancer. Cancer Discov; 5(1); 52–63. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 1

Abstract In response to inflammation, pancreatic acinar cells can undergo acinar-to-ductal metaplasia (ADM), a reprogramming event that induces transdifferentiation to a duct-like phenotype and in the context of additional oncogenic stimulation, contributes to development of pancreatic cancer. The signalling mechanisms underlying pancreatitis-inducing ADM are largely undefined. Our results provide evidence that macrophages infiltrating the pancreas drive this transdifferentiation process. We identify the macrophage-secreted inflammatory cytokines RANTES and TNFα as mediators of such signaling. Both RANTES and TNFα induce ADM through activation of nuclear factor κ-B and its target genes involved in regulating survival, proliferation and degradation of extracellular matrix. In particular we identify matrix metalloproteinases (MMPs) as targets that drive ADM, and provide in vivo data suggesting that MMP inhibitors may be efficiently applied to block pancreatitis-induced ADM in therapy. Citation Format: Geou-yarh Liou, Heike Doeppler, Peter Storz. Macrophage-secreted cytokines drive acinar-to-ductal metaplasia of the pancreas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-342. doi:10.1158/1538-7445.AM2013-LB-342

GH is an important regulator of body growth and composition as well as numerous other metabolic processes. In particular, liver plays a key role in the GH/IGF-I axis, because the majority of circulating “endocrine” IGF-I results from GH-stimulated liver IGF-I production. To develop a better understanding of the role of liver in the overall function of GH, we generated a strain of mice with liver-specific GH receptor (GHR) gene knockout (LiGHRKO mice). LiGHRKO mice had a 90% decrease in circulating IGF-I levels, a 300% increase in circulating GH, and significant changes in IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, IGFBP-5, and IGFBP-7. LiGHRKO mice were smaller than controls, with body length and body weight being significantly decreased in both sexes. Analysis of body composition over time revealed a pattern similar to those found in GH transgenic mice; that is, LiGHRKO mice had a higher percentage of body fat at early ages followed by lower percentage of body fat in adulthood. Local IGF-I mRNA levels were significantly increased in skeletal muscle and select adipose tissue depots. Grip strength was increased in LiGHRKO mice. Finally, circulating levels of leptin, resistin, and adiponectin were increased in LiGHRKO mice. In conclusion, LiGHRKO mice are smaller despite increased local mRNA expression of IGF-I in several tissues, suggesting that liver-derived IGF-I is indeed important for normal body growth. Furthermore, our data suggest that novel GH-dependent cross talk between liver and adipose is important for regulation of adipokines in vivo.