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Pancreatic Neoplasms: HELP
Articles by Weiwei Wu
Based on 4 articles published since 2010
(Why 4 articles?)
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Between 2010 and 2020, Weiwei Wu wrote the following 4 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling. 2016

Kong, Bo / Wu, Weiwei / Cheng, Tao / Schlitter, Anna Melissa / Qian, Chengjia / Bruns, Philipp / Jian, Ziying / Jäger, Carsten / Regel, Ivonne / Raulefs, Susanne / Behler, Nora / Irmler, Martin / Beckers, Johannes / Friess, Helmut / Erkan, Mert / Siveke, Jens T / Tannapfel, Andrea / Hahn, Stephan A / Theis, Fabian J / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · Department of Surgery, Technische Universität München (TUM), Munich, Germany Institute of Computational Biology, Helmholtz-Zentrum München, Munich, Germany. · Institute of Experimental Genetics (IEG), Helmholtz-Zentrum München, Munich, Germany. · Institute of Experimental Genetics (IEG), Helmholtz-Zentrum München, Munich, Germany Technische Universität München, Chair of Experimental Genetics, Freising, Germany Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany. · Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Department of Gastroenterology, TUM, Munich, Germany. · Institute of Pathology, Ruhr-University Bochum, Bochum, Germany. · Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. · Institute of Computational Biology, Helmholtz-Zentrum München, Munich, Germany. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Gut · Pubmed #25601637.

ABSTRACT: OBJECTIVE: Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity. DESIGN: We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material. RESULTS: Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype. CONCLUSIONS: These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.

2 Article Pancreas-specific activation of mTOR and loss of p53 induce tumors reminiscent of acinar cell carcinoma. 2015

Kong, Bo / Cheng, Tao / Qian, Chengjia / Wu, Weiwei / Steiger, Katja / Cao, Jing / Schlitter, Anna Melissa / Regel, Ivonne / Raulefs, Susanne / Friess, Helmut / Erkan, Mert / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · Department of Surgery, Koc School of Medicine, Istanbul, Turkey. · Institute of Pathology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany. · Royal Liverpool and Broadgreen University Hospitals, Liverpool, UK. · Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. cwmichalski@gmail.com. ·Mol Cancer · Pubmed #26683340.

ABSTRACT: BACKGROUND: Pancreatic acinar cell carcinoma (ACC) is a rare tumor entity with an unfavorable prognosis. Recent whole-exome sequencing identified p53 mutations in a subset of human ACC. Activation of the mammalian target of rapamycin (mTOR) pathway is associated with various pancreatic neoplasms. We thus aimed at analyzing whether activation of mTOR with a concomitant loss of p53 may initiate ACC. METHODS: We generated transgenic mouse models in which mTOR was hyperactivated through pancreas-specific, homozygous tuberous sclerosis 1 (Tsc1) deficiency, with or without deletion of p53 (Tsc1 (-/-) and Tsc1 (-/-) ; p53 (-/-) ). Activity of mTOR signaling was investigated using mouse tissues and isolated murine cell lines. Human ACC specimens were used to corroborate the findings from the transgenic mouse models. RESULTS: Hyperactive mTOR signaling in Tsc1 (-/-) mice was not oncogenic but rather induced a near-complete loss of the pancreatic acinar compartment. Acinar cells were lost as a result of apoptosis which was associated with p53 activation. Concomitantly, ductal cells were enriched. Ablation of p53 in Tsc1-deficient mice prevented acinar cell death but promoted formation of acinar cells with severe nuclear abnormalities. One out of seven Tsc1 (-/-) ; p53 (-/-) animals developed pancreatic tumors showing a distinctive tumor morphology, reminiscent of human ACC. Hyperactive mTOR signaling was also detected in a subset of human ACC. CONCLUSION: Hyperactive mTOR signaling combined with loss of p53 in mice induces tumors similar to human ACC.

3 Article Hypoxia-induced endoplasmic reticulum stress characterizes a necrotic phenotype of pancreatic cancer. 2015

Kong, Bo / Cheng, Tao / Wu, Weiwei / Regel, Ivonne / Raulefs, Susanne / Friess, Helmut / Erkan, Mert / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Institute of Pathology, Medical University Innsbruck, Innsbruck, Austria. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Oncotarget · Pubmed #26452217.

ABSTRACT: Stromal fibrosis and tissue necrosis are major histological sequelae of hypoxia. The hypoxia-to-fibrosis sequence is well-documented in pancreatic ductal adenocarcinoma (PDAC). However, hypoxic and necrotic PDAC phenotypes are insufficiently characterized. Recently, reduction of tuberous sclerosis expression in mice together with oncogenic Kras demonstrated a rapidly metastasizing phenotype with histologically eccentric necrosis, transitional hypoxia and devascularisation. We established cell lines from these tumors and transplanted them orthotopically into wild-type mice to test their abilities to recapitulate the histological features of the primary lesions. Notably, the necrotic phenotype was reproduced by only a subset of cell lines while others gave rise to dedifferentiated tumors with significantly reduced necrosis. In vitro analysis of the necrotic tumor-inducing cell lines revealed that these cells released a significant amount of vascular endothelial growth factor A (Vegfa). However, its release was not further increased under hypoxic conditions. Defective hypoxia-induced Vegfa secretion was not due to impaired Vegfa transcription or hypoxia-inducible factor 1-alpha activation, but rather a result of hypoxia-induced endoplasmic reticulum (ER) stress. We thus identified hypoxia-induced ER stress as an important pathway in PDACs with tissue necrosis and rapid metastasis.

4 Article A common genetic variation of melanoma inhibitory activity-2 labels a subtype of pancreatic adenocarcinoma with high endoplasmic reticulum stress levels. 2015

Kong, Bo / Wu, Weiwei / Valkovska, Nataliya / Jäger, Carsten / Hong, Xin / Nitsche, Ulrich / Friess, Helmut / Esposito, Irene / Erkan, Mert / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München, Munich, Germany. · Institute of Pathology, Technische Universität München, Munich, Germany. · Department of Surgery, Koc School of Medicine, Istanbul, Turkey. · Department of Surgery, University of Heidelberg, Germany. ·Sci Rep · Pubmed #25657029.

ABSTRACT: HNF1 homeobox A (HNF1A)-mediated gene expression constitutes an essential component of the secretory pathway in the exocrine pancreas. Melanoma inhibitory activity 2 (MIA2), a protein facilitating protein secretion, is an HNF1A target. Protein secretion is precisely coordinated by the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) system. Here, we demonstrate that HNFA and MIA2 are expressed in a subset of human PDAC tissues and that HNF1A induced MIA2 in vitro. We identified a common germline variant of MIA2 (c.A617G: p.I141M) associated with a secretory defect of the MIA2 protein in PDAC cells. Patients carrying MIA2(I141M) survived longer after tumor resection but the survival benefit was restricted to those patients who received adjuvant chemotherapy. The MIA2(I141M) variant was associated with high expression of ER stress/UPR genes--in particular those of the ERN1/XBP arm--in human PDAC samples. Accordingly, PDAC cell lines expressing the MIA2(I141M) variant expressed high levels of ERN1 and were more sensitive to gemcitabine. These findings define an interaction between the common MIA2(I141M) variant and the ER stress/UPR system and specify a subgroup of PDAC patients who are more likely to benefit from adjuvant chemotherapy.