Junior research group „tumor progression and immune escape“

PD Dr. Jörg Wischhusen (wischhusen_j@klinik.uni-wuerzburg.de; 0931 201 25291)

(link to German version)

The junior research group (Principal Investigator: PD Dr. Jörg Wischhusen) investigates mechanisms which enable tumor cells to escape from cancer immunosurveillance. In this context, a special focus is placed upon classical and non-classical members of the TGF-b superfamily as the pro-migratory, pro-invasive and angiogenesis-promoting properties of TGF-b are essential for the progression of various malignancies. Moreover, TGF-b displays stronger immune-inibitory functions than any other cytokine and can thus contribute to tumor immune escape. Further projects explore the role of miRNAs for TGF-b dependent immunosuppression (in cooperation with the Max-Planck Institute for Biochemistry in Munich), the potential immunomodulatory function of endogenous hormones in ovarian cancer and the immunological characteristics of cancer stem cells. All in vitro findings can be validated in vivo using a genetically driven, inducible mouse model for endometrioid ovarian carcinomas.

The junior research group is supported by the Interdisciplinary Center for Clinical Research (IZKF), the German research council (DFG), the German Cancer Foundation, the Ministry for Education and Research (BMBF), the Graduate School for Life Sciences (GSLS) and by partners in industry.

(PD Dr. rer. nat. Jörg Wischhusen, Dr. med. Mathias Krockenberger, Dr. med. Stefan Heuer, Dr. med. Joachim Diessner,  Dipl.-biol. Anoop Chandran, Dipl.-biol. Markus Junker, Dipl.-biol. Ahmed Adel Seida, MTA Monika Ossadnik, cand. med. Florian Reim, cand. med. Theresa Martens, cand. med. Steffi Neukamm, cand. med. Louisa Schminke, cand. med. Kathrin Becker).

With additional funding from the IZKF and in close association with the junior research group, Dr. Sebastian Häusler and co-workers investigate the role of ATP-degrading and adenosine-generating ectonucleotidases CD39 and CD73 for interactions between ovarian cancer cells, tumor-associated macrophages and the host immune system in vitro und in vivo.

(Dr. med. Sebastian FM Häusler, Dipl.-biol. Itsaso Montalban del Barrio, cand. med. Jenny Strohschein).

Another key aspect addressed by the junior research group is the development of new immune-based strategies for the early detection of gynaecological diseases. This has led to the discovery of specific miRNA profiles in the blood of ovarian cancer patients which might form the basis for a diagnostic test. The biological basis for the observed phenomenon is still unclear. Both “exosomes” (small vesicles secreted by a wide range of mammalian cell types including tumor cells) and altered immune phenotypes are likely to contribute. Accordingly, such miRNA fingerprints might become useful in order to screen for diseases with high inflammatory potential (e.g. ovarian cancer, lung cancer, multiple sclerosis).

(Dr. med. Sebastian FM Häusler, PD Dr. Jörg Wischhusen, MTA N.N.)

selected publications (since 2006) 

• eller, A., ..., Wischhusen, J., Häusler S., Dietl, J., ..., Franke, A., Meese, E., Towards discovering the blood-born miRNome of human diseases, Nature Methods, epub 2011 Sep 04.

• Roth P, Wischhusen J, Happold C, Chandran PA, Hofer S, Eisele G, Weller M, Keller A. A specific miRNA signature in the peripheral blood of glioblastoma patients. J Neurochem. 2011 Aug;118(3):449-57.

• Mittelbronn M, Platten M, Zeiner P, Dombrowski Y, Frank B, Zachskorn C, Harter PN, Weller M, Wischhusen J. Macrophage migration inhibitory factor (MIF) expression in human malignant gliomas contributes to immune escape and tumour progression. Acta Neuropathol. 2011 Jul 21 [Epub ahead of print].

• Häusler, S., Montalban del Barrio, I., Strohschein, J., Chandran, A.P., Engel, J.B., Hönig, A., Ossadnik, M., Horn, E., Fischer, B.,  Krockenberger, M., Heuer, S., Sheida, A, Junker, M., Kneitz, H., Kloor, D., Klotz K.N., Dietl, J., Wischhusen, J., Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A dependent suppression of T cell function and NK cell cytotoxicity, Cancer Immunol Immunother. 2011 Jun 3. [Epub ahead of print]

• Houben R, Hesbacher S, Schmid C, Kauczok CS, Flohr U, Haferkamp S, Müller C, Schrama D, Wischhusen J, Becker JC. High-level expression of wild-type p53 in melanoma cells is frequently associated with inactivity in p53 reporter gene assays. PLoS ONE accepted

• Wischhusen J, Diessner J, Becker K, Hönig A. Targeting of pre-existing and induced breast cancer stem cells with HER2-specific immunotherapeutics and NK cells. J. Immunol. 186(S1):165.18, 2011

• Honig, A., Engel, J.B., Segerer, S.E., Kranke, P., Häusler, S., Würfel, W., Pregnancy-triggered antiphospholipid syndrome in a patient with multiple late miscarriages. Hum Reprod. 2010 Nov;25(11):2753-4.

• Häusler, S., Ossadnik, M., Horn, E., Heuer, S., Dietl, J., Wischhusen, J., a cell-based luciferase-dependent assay for the quantitative determination of free extracellular adenosine with paracrine signaling activity, J Immunol Methods, 2010 Sep 30, 361(1-2)

• Roth P, Junker M, Tritschler I, Mittelbronn M, Dombrowski Y, Breit SN, Tabatabai G, Wick W, Weller M, Wischhusen J. GDF-15 contributes to proliferation and immune escape of malignant gliomas. Clin Cancer Res. 16(15):3851-9, 2010

• Häusler, S., Keller, A., Chandran, P.A., Ziegler, K., Zipp, K., Heuer, S., Krockenberger, M., Engel, J.B., Hönig, A., Scheffler, M., Dietl, J., Wischhusen, J., Whole blood-derived miRNA profiles as potential new tools for ovarian cancer screening. Br J Cancer. 2010 Aug 24;103(5):693-700.

• Häusler SFM, Keller A, Chandran A, Wischhusen J. A new approach for ovarian cancer screening - characterization of miRNA profiles in peripheral blood. Eur. J. Human Genetics, 18(S1): 28, 2010.

• Lottaz C, Beier D, Meyer K, Kumar P, Hermann A, Schwarz J, Junker M, Oefner PJ, Bogdahn U, Wischhusen J, Spang R, Storch A, Beier CP. Transcriptional profiles of CD133+ and CD133- glioblastoma-derived cancer stem cell lines suggest different cells of origin, Cancer Res., 70(5):2030–40, 2010

• Heidbrink, C.*, Häusler, S*., Buttmann, M., Ossadnik, M., Strik, H.M., Keller, A., Buck, D., Verbraak, E., van Meurs, M., Krockenberger, M., Mehling, M., Mittelbronn, M., Laman, J.D., Wiendl, H., Wischhusen, J., Reduced cortisol levels in cerebrospinal fluid and differential distribution of 11beta-hydroxysteroid dehydrogenases in multiple sclerosis: implications for lesion pathogenesis. Brain Behav Immun. 2010 Aug;24(6):975-84. *: both autors contributed equally

• Galmbacher K, Hotz C, Heisig M, Wischhusen J, Galmiche A, Bergmann B, Gentschev I, Goebel W, Rapp UR, Fensterle J. Shigella Mediated Depletion of Macrophages in a Murine Breast Cancer Model Is Associated with Tumor Regression. PLoS ONE, http://dx.plos.org/10.1371/journal.pone.0009572.

• Reim F, Dombrowski Y, Ritter C, Buttmann M, Häusler S, Ossadnik M, Krockenberger M, Beier D, Beier CP, Dietl J, Becker JC, Hönig A, Wischhusen J. Immunoselection of breast and ovarian cancer cells with trastuzumab and NK cells: Selective escape of CD44high/CD24low/HER2low breast cancer stem cells. Cancer Res. 69(20):8058-66, 2009.

• Krockenberger M, Engel JB, Kolb J, Dombrowski Y, Häusler SF, Kohrenhagen N, Dietl J, Wischhusen J, Hönig A. Macrophage migration inhibitory factor expression in cervical cancer. J Cancer Res Clin Oncol. 2009.

• Engel JB, Schönhals T, Weidler C, Häusler S, Krockenberger M, Rieger L, Dietl J, Wischhusen J, Hönig A. Tubulin inhibitor AEZS 112 inhibits the growth of experimental human ovarian and endometrial cancers irrespective of caspase inhibition. Oncol Rep. 22(2):361-7, 2009.

• Waschbisch A, Wintterle S, Lochmüller H, Walter MC, Wischhusen J, Kieseier BC, Wiendl H. Human muscle cells express the costimulatory molecule B7-H3, which modulates muscle-immune interactions. Arthritis Rheum. 58(11):3600-8, 2008.

• Engel JB, Hönig A, Schönhals T, Weidler C, Häusler S, Krockenberger M, Grünewald TG, Dombrowski Y, Rieger L, Dietl J, Wischhusen J. Perifosine inhibits growth of human experimental endometrial cancers by blockade of AKT phosphorylation. Eur J Obstet Gynecol Reprod Biol. 2008.

• Beier D, Röhrl S, Pillai DR, Schwarz S, Kunz-Schughart LA, Leukel P, Proescholdt M, Brawanski A, Bogdahn U, Trampe-Kieslich A, Giebel B, Wischhusen J, Reifenberger G, Hau P, Beier CP. Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Res. 15;68(14):5706-15, 2008.

• Krockenberger M, Dombrowski Y, Weidler C, Ossadnik M, Hönig A, Häusler S, Voigt H, Becker JC, Leng L, Steinle A, Weller M, Bucala R, Dietl J and Wischhusen J. Macrophage migration inhibitory factor (MIF) contributes to the immune escape of ovarian cancer by downregulating NKG2D. J Immunol, 180(11):7338-48, 2008.

• Weinmann L, Wischhusen J, Demma MJ, Naumann U, Roth P, DasMahapatra P, Weller M. A novel p53 rescue compound induces p53-dependent growth arrest and sensitises glioma cells to Apo2L/TRAIL-induced apoptosis. Cell Death Differ. 15(4):718-29, 2008.

• Beier D, Wischhusen J, Dietmaier W, Hau P, Proescholdt M, Brawanski A, Bogdahn U and Beier CP. CD133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors. Brain Pathol. 18(3):370-7, 2008.

• Mittelbronn M, Simon P, Löffler C, Capper D, Bunz B, Harter P, Schlaszus H, Schleich A, Tabatabai G, Goeppert B, Meyermann R, Weller M and Wischhusen J. Elevated HLA-E levels in human glioblastomas but not in grade I to III astrocytomas correlate with infiltrating CD8⁺ cells. J Neuroimmunol 189(1-2):50-8, 2007.

• Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U and Beier CP. CD133⁺ and CD133^- glioblastoma derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 67(9):4010-5, 2007.

• Eisele G, Wischhusen J, Mittelbronn M, Meyermann R, Waldhauer I, Steinle A, Weller M, Friese MA. TGF-b and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain 129(Pt 9):2416-25, 2006.

• Roth P, Aulwurm S, Gekel I, Beier D, Sperry RG, Mittelbronn M, Meyermann R, Beaman KD, Weller M, Wischhusen J. Regeneration and tolerance factor (RTF): a novel mediator of glioblastoma-associated immunosuppression. Cancer Res. 66(7):3852-8, 2006.

• Schreiner B, Voss J, Wischhusen J, Dombrowski Y, Steinle A, Lochmüller H, Dalakas M, Melms A, Wiendl H. Expression of toll-like receptors by human muscle cells in vitro and in vivo: TLR3 is highly expressed in inflammatory and HIV myopathies, mediates IL-8 release, and up-regulation of NKG2D-ligands. FASEB J. 20(1):118-20, 2006.

review articles

• Dietl, J., Wischhusen, J., Häusler, S., The redundant post-reproductive Fallopian Tube: better removed?, Hum Reprod, epub 2011 Aug 16.

• Dietl J, Wischhusen J. The forgotten fallopian tube. Nature Rev. Cancer 11(3):227, 2011.

• Häusler, S., tumor immune escape bei gynäkologischen Tumoren, Ärztliche Praxis Gynäkologie, 2011 Mar.

• Menaa F, Houben R, Eyrich M, Broecker EB, Becker JC, Wischhusen J. Stem Cells, Melanoma and Cancer Stem Cells: the Good, the Bad and the Evil? Giornale Ital.Dermat.Venereol. 144(3):287-96, 2009.

• Houben R, Wischhusen J, Menaa F, Synwoldt P, Schrama D, Bröcker EB, Becker JC. Melanoma stem cells: targets for successful therapy? J Dtsch Dermatol Ges. 6(7):541-6, 2008.

• Wischhusen J, Waschbisch A and Wiendl H. Immune-refractory cancers and their little helpers – an extended role for immunetolerogenic MHC molecules HLA-G and HLA-E? Semin Cancer Biol. 17(6):459-468, 2007.

• Dietl J, Engel JB, Wischhusen J. The role of regulatory T cells in ovarian cancer. Int J Gynecol Cancer. 17(4):764-70, 2007.