Group description
Name: Kenner, Lukas J.
Title: Univ. Prof. Dr.,
Date of Birth: 08.10.1965
Nationality: Austria
Institution: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Address: Währingerstr.13a, A-1090 Vienna, Austria
Phone: (+43-1) 40160 71210
Fax: (+43-1) 40160 931300
e-mail: lukas.kenner@lbicr.lbg.ac.at

The research group of LK consists currently of 1 Ph.D. student, and three Biomedical Scientists and all focused on transgenic mouse research and the analysis of tumour models as well as human patients tumor samples. Lukas Kenner (LK) is group leader at the Ludwig Boltzmann Institute for Cancer Research (http://lbicr.lbg.ac.at/) and has a group at the Institute of Clinical Pathology, Universitiy Hospital Vienna (AKH) (http://www.meduniwien.ac.at/klinpath/).

The group of LK formed in 2006 and LK supervises several national and international research projects. Together with our partner Company TissueGnosticsTM (http://www.tissuegnostics.com) LK and Biomedical Scientist Michaela Schlederer developed and improved software for protein quantification stained by immunohistochemical or immunofluorescence techniques from tissue slides.One focus of his group is the role of JunB for Lymphoma development, which is partly funded by the FWF and the “Fellinger” Fonds. Further grant money was attracted through international collaboration with groups in Italy and France (www.novussanguis.org) focusing on translational work with mesenchymal stem cells (MSCs). In addition, LK is part of the GenAU (Genome Austria) Inflammobiota project http://gutmicrobiota.univie.ac.at/inflammobiota/) which focuses on the role of Jak/Stat pathway in Inflammatory Bowel Disease (IBD). At the LBI-CR, LK investigates the role of Jak/Stat pathway in prostate cancer development.

Reference center for TissueGnostics at the LBI-CR. Biomedical Scientist Michael Schlederer at the work station quantifying protein expression levels in prostate cancer patient samples with our new HistoQuestTM digital imaging software.

1. Prostate cancer tissue arrays and expression analysis of Androgen receptor and SOCS-1 using TissueQuestTM software. We established 4 tissue arrays of 8 prostate cancer patients before and 8 patients after androgen ablation therapy, as well as 2 prostate samples from non-tumor affected prostates as controls. To compare the expression levels of candidate oncogenes from patients without prostate cancer (PC), normal prostate tissue was included from prostates of patients that underwent a cystectomy operation. Target gene expression analysis was performed using immunofluorescence microscopy and digital image analysis techniques from our Partner TissueGnostics. Suppressors of cytokine signaling (SOCS) proteins regulate development and progression of various malignant diseases. We quantified Androgen Receptor (AR) and Socs-1 protein expression levels. It was previously shown that SOCS-3 is expressed in prostate cancer and its expression is inversely correlated with activation of Stat3. The in vivo protein expression of these oncogenes was measured without the mesenchymal background. The areas containing the mesenchymal cells were deleted to obtain an epithelial cell specific mask for analysis. The results were verified by analysis with the software of TissueQuest™. AR is significantly overexpressed in high- and low grade prostate cancers. SOCS-1 expression decreased in samples taken from patients undergoing hormonal therapy but increased in specimens from patients who failed therapy. In summary, we showed that SOCS-1 is expressed in prostate cancer in vivo and acts as a negative growth regulator. This work is done in close collaboration with the excellent partner group of Prof. Zoran Culig at the Medical University of Innsbruck (http://www.zculig.org).
 

Tissue Micro Array (TMA) technology is essential for investigating high numbers of human tissue samples from prostate cancer patients. This TMA compare normal, PIN as well as low and high Gleasongrade prostate cancer patient samples.

 

Digital image analysis from prostate cancer patient samples. Human prostate tissue microarrays (TMAs) were analyzed by immunofluorescence microscopy. Samples were triple stained using DAPI and specific antibodies against tumor specific marker AMACR (FITC) and CK 18 (Rhodamine) using TissueGnostics software.

2. The role of persistent Jak-Stat activation for prostate cancer progression and therapy. An important treatment strategy for prostate cancer patients is androgen depletion. After increased time (more then two years), however, most patients suffer from relapse due to development of androgen insensitivity. This is frequently caused by a mutated hormone-independent or amplified androgen receptor that occurs after 3-4 years of androgen ablation therapy. We took advantage of patient samples before and after androgen ablation therapy, (but therapy was maximally performed for two to twelve months) where we investigated the role of persistent Jak/Stat activation in the prostate cancer tissue arrays before and after chemotherapy. In this study we use immunohistochemistry (IHC), which increases the sensitivity. Together with the new analysis method HistoQuestTM, a precise and quick quantification of protein expression levels from patient samples is possible. Quantitation revealed differential expression levels of total Stat3/Stat5 as well as activated P-Y-Stat3/P-Y-Stat5 and important downstream targets after chemotherapy, implicated in Jak-Stat activation. At the moment we are investigating the effects on essential cell cycle regulators using the above described methods or proteins involved in survival, growth or tissue invasion of prostate cancer cells.
 

 

IHC analysis from 16 patient samples before and after androgen ablation. Human prostate tissue arrays were analyzed by IHC microscopy - staining using specific antibodies against P-Y-Stat3. Note the increasing expression of P-Y-Stat3 in PIN and prostate carcinoma (PC) epithelial cells compared to normal epithelial samples. However, reduced P-Y-Stat3 expression levels were also observed in PIN and PC samples after androgen ablation therapy.

 

 

IHC analysis before and after Androgen ablation using HistoQuestTM software. Human prostate tissue arrays from 16 patients were quantified by HistoQuest analysis and IHC microscopy staining using specific antibodies against P-Y-Stat3 and hemalaun counterstaining.

3. Role of JunB and cJun in NPM-ALk induced Anaplastic Large T-Cell Lymphoma (ALCL)

ALCL is a highly malignant form of Non-Hodgkin’s lymphoma and frequently associated with a chromosomal translocation generating the oncogenic fusion protein NPM-ALK. We take advantage of a NPM-ALK transgenic mouse model for ALCL lymphomagenesis driven by the human CD4 promoter (Chiarle et al. 2003). These mice develop high malignant T-cell lymphomas. Human ALCLs were recently shown to constitutively overexpress the AP-1 proteins c-Jun and JunB. The role of c-Jun and JunB in T-cell lymphomas has not been fully understood. Interestingly, a tumor suppressive role of JunB was recently demonstrated in mice lacking JunB in the myeloid lineage which develop a CML-like disease. In this project we use mice carrying floxed alleles of JunB and/or c-Jun and the CD4-Cre mice which specifically delete these genes in T-cells. We conditionally delete c-Jun and JunB in NPM-ALK induced lymphomas to study the requirement of AP-1 in lymphoma formation. In this context we analyze latency, proliferation and the apoptotic index of transformed cells. These experiments define the function of AP-1 targets as potential therapeutic target in T-cell lymphomas before and/or after lymphoma formation. 

Mice carrying the NPM-ALK fusion gene under the human CD4 promoter (Chiarle et al. 2003) is the backbone of our experiments. We conditionally delete JunB and cJun in T-cells taking advantage of a CD4 Cre mouse deleter strain.

3. Aims and milestones
In a study published in Nat. Cell Biol. 2008 we could demonstrate that the loss of JunB expression in the epidermis of adult mice affects the skin, the proliferation of haematopoietic cells and bone formation. G-CSF is a direct transcriptional target of JunB and mutant epidermis releases large amounts of G-CSF that reach high systemic levels and cause skin ulcerations, myeloproliferative disease and low bone mass. The absence of G-CSF significantly improves hyperkeratosis and prevents the development of myeloproliferative disease, but does not affect bone loss. This study describes a mechanism by which the absence of JunB in epithelial cells causes multi-organ disease, suggesting that the epidermis can act as an endocrine-like organ. Increasing numbers of interesting phenotypes in the LBI-CR, due to breeding “conventional” conditional knock out mice, and by establishing the Multi-Hit technology, bring the molecular pathologist to the cutting edge of successful science. In addition to his own projects, LK supports colleagues with high quality morphology and digital image analysis (including histochemistry, immunofluorescence and electronmicroscopy). Moreover, LK is involved in patient sample diagnosis at the University hospital Vienna (AKH) and has therefore a very close clinical connection. The group of LK is currently investigating the Jak/Stat pathway both in human PC patient samples and in conditional knock out mice, also in concerted action with the other expert groups at the LBI. Together with TissueGnostics we established technical approaches to analyze, quantify and depict expression levels of up to 4 different proteins simultaneously in vivo. Using this technological platform we have an effective tool for correlating different genetic pathways in mouse and human tumor samples.

Group Members:
PhD Student: Jan Pencik
Biomedical Scientist: Michaela Schlederer
Biomedical Scientist: Elisabeth Gurnhofer (MUW)
Biomedical Scientist: Susi Heider (MUW)

Current collaborations of group LK
The group of LK holds long term international and national collaborations. It was essential for joint publications, but also successful grant money attraction:

Anton Wutz, IMP, Vienna, Austria on epigenetic gene silencing in NPM-ALK induced lymphomagenesis.

Christian Seiser, Max F. Perutz Laboratories, Medical University of Vienna, Vienna Biocenter, Vienna, Austria on HDAC regulated stem cell differentiation and tumorigenesis.

Zoran Culig, Medical University Innsbruck, Urology Department, on Stat3 signaling and invasion in prostate cancer.

Helmut Klocker, Medical University Innsbruck, Urology Department, on the role of MID-1 in mouse and human prostate cancer.
Erwin F. Wagner, CNIO Madrid, Spain on the role of JunB in leukemogenesis and autoimmunity.

Fabrice Gouilleux, University Picardie Jules Verne, INSERM 0351, Amiens, France, on GIST and activated forms of Stat3.

Sebastian Bauer, Institute of Cancer Research of the Internal Medicine Department, University Duisburg-Essen, Germany on GIST mutations of c-KIT in human GIST tumor formation.

Jan Tuckermann, Leibniz Institute for Aging Research, Jena, Germany, on transgenic Stat5 and GR mice in inflammatory diseases.

Konrad Hochedlinger, Harvard Stem Cell Institute, Cambridge, MA, U.S.A., on stem cell induction using viral vectors.

Colin McGuckin
Cell Therapy Research Institute (CTI), University of Lyon, on MSC differentiation and regulation of adult stem cell development as well as Jak/Stat pathway in stem cell differentiation and tumorigenesis: Collaboration in the Novussanguis Consortium.

Mariusz Ratajczak, University of Luiseville, Stem cell Institute at James Brown Cancer Center, KY, USA, on cancer stem cell induced rhabdomyosarcoma development.

Giorgio Inghirami, Friedrich Schiller University, Jena, Germany, Center for Experimental Research and Medical Studies, University of Torino, Italy on the role of AP-1 in NPM-ALK induced human- and mouse lymphomagenesis.

Greg Hannon, Cold Spring Harbor (CSH) Laboratory, NY, on the role of miRNA in umbilical cordblood stemcell differentiation.

Markus Heim, Biomedical Department, University Hospital Basel, Switzerland, on liver cancer.

Raffaella Sordella, Cold Spring Harbor (CSH) Laboratory, NY, on the role IL-6/Stat3 pathway in lung carcinoma.

Visit and talk of Lukas Kenner at the CNIO/Madrid and University of Madrid 2009. From left to right: Mariano Barbacid (Director, CNIO), Elena Postigo-Solana (Univ. Madrid), Erwin F. Wagner (Debuty Director CNIO) and Lukas Kenner (LBI-CR) at dinner in downtown Madrid.

 

Visiting scientist Arne Östman, Karolinska Institute and Lukas Kenner discussing joint projects in the Cafè Central, Vienna.

 

 

Visiting scientist Markus Heim, Department for Biomedicine, University Basel enyoing a glass of vine together with Lukas Kenner, after his talk at the LBI-CR in the Heurigen “Feuerwehr Wagner” in Grinzing, Vienna.

Visit and lecture at the CSH Laboratory NY: Greg Hannon and Lukas Kenner talking about the role of miRNAs in tumor development in the CSH cafeteria.

 

 

 

Attachment	Size
Curriculum Vitae LK 12-05-11.doc	46.5 KB