Liou, Geou‐Yarh

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

In response to inflammation, pancreatic acinar cells can undergo acinar-to-ductal metaplasia (ADM), a reprogramming event that induces transdifferentiation to a ductlike phenotype and, in the context of additional oncogenic stimulation, contributes to development of pancreatic cancer. The signaling 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 tumor necrosis factor α (TNF) as mediators of such signaling. Both RANTES and TNF induce ADM through activation of nuclear factor κB 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.

Abstract Pancreatic cancer is the most lethal type of cancer due to its high proliferation, metastasis and resistance to chemotherapy. In pancreatic cancer, pancreatic ductal adenocacinoma (PDAC) is the most common form. Current opinion is that PDAC originates from acinar or centroacinar cells though a process called “acinar-to-ductal metaplasia” (ADM). During ADM, acinar cells undergo a transformation to ductal PanIN (pancreatic intraepithelial neoplasia) cells, which is believed as the first step in PDAC formation. Transforming growth factor α (TGFα) is produced by pancreatic cancer cells and promotes tumor growth. In an ex vivo explant culture system, TGFα transforms murine pancreatic acinar cells into ductal cells. Here we describe a cell signaling pathway that TGFα utilizes to induce acinar-to-ductal transformation. We show that K-ras is downstream of TGFα and is sufficient to drive ADM. We further show the mechanisms that K-ras uses to induce cell structural rearrangement of acinar cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1123. doi:10.1158/1538-7445.AM2011-1123

Some 5 years ago, it was first discovered that mutations in the gene encoding LRRK2 (leucine-rich repeat protein kinase 2) are tightly linked with a subset of familial PD (Parkinson's disease). Before this genetic association, LRRK2 had never been investigated biochemically. Now it is of utmost importance to establish whether LRRK2 is a bona fide kinase in vitro and in vivo and to understand how mutations of LRRK2 lead to the specific loss of dopaminergic neurons in the substantia nigra to cause PD. In spite of tremendous efforts in the research community, there is no consensus with regard to the magnitude of the enzymatic activity of LRRK2 mutant forms that segregate with PD owing, in part, to the lack of a highly sensitive kinase assay system, and it is still unclear whether an abnormal increase in kinase activity is responsible for LRRK2-associated PD. As described in this issue of the Biochemical Journal, Nichols et al. have developed an extensive set of molecular tools, including an optimized peptide substrate for determining in vitro kinase activity of LRRK2, a set of kinase inhibitors that can be used to explore LRRK2 substrate specificity and biology, a much-needed murine-specific antibody for immunoprecipation, and efficient gene-silencing approaches. In the present commentary, we discuss some of the components of this new LRRK2 biochemical toolbox and how they can be used to better understand this enigmatic kinase.