Kliniken & Institute ... Institute Pathologisches Institut... Abteilungen Allgemeine Pathologie ... Forschung Arbeitsgruppen AG Longerich

Longerich lab

Research focus

In most cases carcinogenesis represents a multi-step process with morphologically defined premalignant lesions. In case of hepatocellular neoplasia, these are called dysplastic nodules and precede the development of hepatocellular carcinoma. Furthermore, recent evidence suggested that intrahepatic cholangiocarcinoma, a tumor thought to be derived from the biliary tree, may also develop from hepatocytes.

Although the underlying chronic liver diseases (mainly chronic Hepatitis B and C virus infection, chronic alcohol abuse, metabolic syndrome, genetic hemochromatosis) inducing the development of hepatocyte-derived liver tumors are well defined, the molecular alterations promoting certain steps of tumor initiation and progression remain elusive.

Our research aims at defining driver genes leading to the evolution and progression of human liver carcinomas and to identify mechanisms affecting liver cell plasticity and tumor phenotype. Additionally, we aim at the identification of molecular markers that may be useful for diagnosis, prediction of therapy response and/or therapeutic targeting.

We use comprehensive profiling approaches at DNA and RNA level to identify potential driver genes in phenotypically defined lesions of liver carcinogenesis. These are validated in human samples by molecular pathological approaches (real-time RT-PCR, Western immunoblot, immunohistochemistry, ChIP, Sanger and next generation sequencing) and the resulting candidates are validated in vitro using transfections/infections (siRNA, shRNA, cDNA) as well as CRISPR/Cas9-mediated genomic engineering of liver cell lines. Finally, in vivo analyses are performed using mosaic mouse models.

Current funding:

Deutsche Forschungsgesellschaft

Team

Thomas Longerich, MD thomas.longerich@med.uni-heidelberg.de
Rossella Pellegrino, PhD rossella.pellegrino@med.uni-heidelberg.de
Federico Pinna, PhD federico.pinna@med.uni-heidelberg.de
Ariane Neumann ariane.neumann@med.uni-heidelberg.de
PhD Student (N.N)  
Technician (N.N)  

Selected publications

Schneider AT, Gautheron J, Feoktistova M, Roderburg C, Loosen SH, Roy S, Benz F, Schemmer P, Büchler MW, Nachbur U, Neumann UP, Tolba R, Luedde M, Zucman-Rossi J, Panayotova-Dimitrova D, Leverkus M, Preisinger C, Tacke F, Trautwein C, Longerich T, Vucur M, Luedde T (2017) RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer. Cancer Cell 31:94-109.

Eggert T, Wolter K, Ji J, Ma C, Yevsa T, Klotz S, Medina-Echeverz J, Longerich T, Forgues M, Reisinger F, Heikenwalder M, Wang XW, Zender L, Greten TF (2016) Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression. Cancer Cell 30:533-547

Endig J, Buitrago-Molina LE, Marhenke S, Reisinger F, Saborowski A, Schütt J, Limbourg F, Könecke C, Schreder A, Michael A, Misslitz AC, Healy ME, Geffers R, Clavel T, Haller D, Unger K, Finegold M, Weber A, Manns MP, Longerich T, Heikenwälder M, Vogel A (2016) Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development.  Cancer Cell 30:308-323

Dauch D, Rudalska R, Cossa G, Nault JC, Kang TW, Wuestefeld T, Hohmeyer A, Imbeaud S, Yevsa T, Hoenicke L, Pantsar T, Bozko P, Malek NP, Longerich T, Laufer S, Poso A, Zucman-Rossi J, Eilers M, Zender L (2016) A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med 22:744-753

Ohrnberger S, Thavamani A, Braeuning A, Lipka DB, Kirilov M, Geffers R, Authenrieth SE, Römer M, Zell A, Bonin M, Schwarz M, Schütz G, Schirmacher P, Plass C, Longerich T, Nordheim A (2015) Dysregulated SRF triggers formation of hepatocellular carcinoma. Hepatology 61:979-989

Rudalska R*, Dauch D*, Longerich T, McJunkin K, Wuestefeld T, Kang TW, Hohmeyer A, Pesic M, Leibold J, von Thun A, Schirmacher P, Zuber J, Weiss KH, Powers S, Malek NP, Eilers M, Sipos B, Lowe SW, Geffers R, Laufer S, Zender L (2014) In vivo RNAi screening identifies a mechanism of Sorafenib resistance in liver cancer. Nature Med 20:1138-1146 (shared first authorship)

Tschaharganeh DF, Xue W, Calvisi DF, Evert M, Michurina TV, Dow LE, Banito A, Katz SF, Kastenhuber ER, Weissmueller S, Huang CH, Lechel A, Andersen JB, Capper D, Zender L, Longerich T, Enikolopov G, Lowe SW (2014) p53 dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell 158:579–592

Pellegrino R, Calvisi DF, Neumann O, Kolluru V, Wesely J, Chen X, Wang C, Wuestefeld T, Ladu S, Elgohary N, Bermejo JL, Radlwimmer B, Zörnig M, Zender L, Dombrowski F, Evert M, Schirmacher P, Longerich T (2014) EEF1A2 inactivates p53 via PI3K/AKT/mTOR-dependent stabilization of MDM4 in hepatocellular carcinoma. Hepatology 59:1886-1899

Neumann O, Kesselmeier M, Geffers R, Pellegrino R, Radlwimmer B, Hoffmann K, Ehemann V, Schemmer P, Schirmacher P, Bermejo JL, Longerich T (2012) Methylome analysis and integrative profiling of human HCCs identify novel protumorigenic factors. Hepatology 56:1817-1827

Longerich T, Müller MM, Breuhahn K, Schirmacher P, Benner A, Heiss C (2012) Oncogenetic tree modeling of human hepatocarcinogenesis. Int J Cancer 130:575-583

Collaborations

Prof. Dr. P. Angel, Divisions of Signal Transduction and Growth Control, German Cancer Research Center, Heidelberg

Dr. Diego Calvisi, Prof. Dr. Frank Dombrowski, Institute of Pathology, Ernst-Moritz-Arndt-University Greifswald

Prof. Dr. Uta Drebber, Prof. Dr. M. Odenthal, Institute of Pathology, University of Cologne

Prof. Dr. Matthias Evert, Institute of Pathology, University Hospital Regensburg

Dr. Robert Geffers, Genome Analytics, Helmholtz Centre for Infection Research

Prof. Dr. Tim Greten, Gastrointestinal Malignancy Section, Nationale Cancer Institute, Center for Cancer Research, Bethesda, USA

Prof. Dr. Maria Guido, Surgical Pathology & Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Italy

Prof. Dr. J Lorenzo-Bermejo, Biostatistics, Department of Medical Biometry, University Hospital Heidelberg

Prof. Dr. T. Lüdde, Department of Medicine III, University Hospital RWTH Aachen

Prof. Dr. Alfred Nordheim, Department of Molecular Biology, Interfacultary Institute for Cell Biology, University of Tübingen

Prof. Dr. Young Nyun Park, Institute of Pathology, Yonsei University College of Medicine, Seoul, Korea

Dr. Britta Skawran, Prof. Dr. Brigitte Schlegelberger, Institute of Cell and Molecular Pathology, Hannover Medical School

Prof. Dr. F. Tacke, Department of Medicine III, University Hospital RWTH Aachen

Prof. Dr. Arndt Vogel, Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School

Prof. Dr. Lars Zender, Internal Medicine VIII – Clinical Tumorbiology, University Hospital Tübingen

Prof. Dr. Martin Zörnig, Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt/Main