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Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates(More)
Physiological levels of Kras(G12D) are sufficient to induce pancreatic intraepithelial neoplasias (PanINs); the mechanisms that drive PanIN progression are unknown. Here, we establish that, in addition to oncogenic Kras(G12D), IL-6 transsignaling-dependent activation of Stat3/Socs3 is required to promote PanIN progression and pancreatic ductal(More)
Growth factors have been implicated in pancreatic carcinogenesis. In this study we analyzed the effect of Tgfa overexpression in addition to mutant Kras(G12D) by crossing Elastase-Tgfa mice with p48(+/Cre);Kras(+/LSL-G12D) mice. We show that concomitant expression of TGFalpha and Kras(G12D) accelerates the progression of mPanIN lesions to metastatic(More)
The chemokine receptor CXCR5 is expressed by B cells and certain T cells and controls their migration into and within lymph nodes. Its ligand BCA-1/CXCL13 is present in lymph nodes and spleen and also in the liver. Surprisingly, we detected CXCR5 in several mouse and human carcinoma cell lines. CXCR5 was particularly prominent in pancreatic carcinoma cell(More)
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC(More)
Intraductal papillary neoplasms of the bile duct are still poorly characterized regarding (1) their molecular alterations during the development to invasive carcinomas, (2) their subtype stratification and (3) their biological behavior. We performed a multicenter study that analyzed these issues in a large European cohort. Intraductal papillary neoplasms of(More)
Pancreatic cancer is one of the most fatal malignancies lacking effective therapies. Notch signaling is a key regulator of cell fate specification and pancreatic cancer development; however, the role of individual Notch receptors and downstream signaling is largely unknown. Here, we show that Notch2 is predominantly expressed in ductal cells and pancreatic(More)
BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease without effective chemopreventive or therapeutic approaches. Although the role of oncogenic Kras in initiating development of PDAC is well established, downstream targets of aberrant Ras signaling are poorly understood. Acinar-ductal metaplasia (ADM) appears to be an important(More)
Global deregulation of DNA methylation is one of the crucial causes of hepato cellular carcinoma (HCC). It has been reported that the anti-cancer drug 5-azacytidine (5-AZA) mediates the activation of tumor suppressor genes through passive demethylation by inhibiting DNMT1. Recent evidence suggests that active demethylation which is mediated by ten-eleven(More)
Trp53(+/-) mice overexpressing Tgfalpha in a pancreas-specific manner represent a well-established animal model for pancreatic cancer. In this study we analyzed 38 pancreatic adenocarcinomas of these mice for secondary genomic changes by comparative genomic hybridization (CGH), loss of heterozygosity (LOH) analysis, real-time PCR, and methylation-specific(More)