Gastl Guenther, Univ.-Prof. Dr.med.univ.

University / Clinic: Department of Internal Medicine
Institute: Division of Haematology and Oncology
 
Research Area: Tumor Profiling

Email: Guenther.Gastl@i-med.ac.at
Web:  


Research Topic:
It is clinically established that malignant tumors induce immune tolerance and escape via cancer-associated immunosuppressive mechanisms such as ineffective co-stimulation, impaired CD4+ T cell help and/or inhibitory signals by regulatory T cells. Due to these mechanisms of tumor immune evasion, a successful anti-cancer immunotherapy must regain e.g. the CD8+ cytotoxic T lymphocyte ability to effectively induce eradication of cancer cells in vivo. Recently, gene ablation of E3 ubiquitin ligase Cbl-B has been shown to exert a dramatic enhancement on T cell activation responses in mouse tumor models relevant for human cancers. Therefore targeting Cbl-B expression and/or function may provide the unique therapeutic option of antagonizing this T cell anergy observed in cancer patients. In course of our studies we defined Cbl-B as the critical PKCtheta substrate in peripheral T cells and this PKCtheta/Cbl-B interaction proved to be the rate-limiting step in the anergy avoidance pathway of CD28 co-stimulation. Indeed, genetic proof has been accomplished by a nearly complete rescue of the opposite T cell phenotypes of the Cbl-B single (immuneaugmentation) and PKCtheta single (immunesuppresssion) KOs in a Cbl-B/PKCtheta double-KO ex vivo and in vivo. PKCtheta and Cbl-B thereby appear to represent antagonistic participants in a critical pathway governing the decision making between unresponsiveness and productive T cell activation including tumor immuno-surveillance in vivo. Our goal for the second funding period is to gain further insight in the biochemical mechanisms of this PKCtheta/Cbl-B antagonism, in particular the critical PKCtheta-mediated phosphorylation sites on Cbl-B governing downstream ubiquitinylation patterns (Lys48- and/or Lys63-linked) including the identification of specific targets of Cbl-B in the central-staged pathways leading to AP-1, NF-AT & NF-kappaB, together regulating the activation thresholds of T cells to perform effective tumor cell clearance in vivo.

Project:
  GRP78 in tumor resistance
details ...

Selected publications:
 
  Martowicz A, Rainer J, Lelong J, Spizzo G, Gastl G, Untergasser G
EpCAM overexpression prolongs proliferative capacity of primary human breast epithelial cells and supports hyperplastic growth
Mol Cancer. 2013 Jun 10;12(1):56.

  Martowicz A, Spizzo G, Gastl G, Untergasser G
Phenotype-dependent effects of EpCAM expression on growth and invasion of human breast cancer cell lines.
BMC Cancer. 2012 Oct 30;12:501.

  Gostner J, Fong D, Wrulich O, Lehne F, Zitt M, Hermann M, Krobitsch S, Martowicz A, Gastl G, Spizzo G
Effects of EpCAM overexpression on human breast cancer cell lines.
BMC Cancer. 2011 Jan 31;11:45.

  Lutz-Nicoladoni C, Wallner S, Stoitzner P, Pircher M, Gruber T, Wolf A, Gastl G, Penninger J, Baier G, Wolf D
Reinforcement of cancer immunotherapy by adoptive transfer of cblb-deficient CD8(+) T cells combined with a DC vaccine.
Immunol Cell Biol. 2011

  Medinger M, Tzankov A, Kern J, Pircher A, Hermann M, Ott H, Gastl G, Untergasser G, Gunsilius E
Increased Dkk3 protein expression in platelets and megakaryocytes of patients with myeloproliferative neoplasms.
Thromb Haemost. 2011 Jan 3;105(1):72-80.

  Gruber T, Hermann-Kleiter N, Hinterleitner R, Fresser F, Schneider R, Gastl G, Penninger J, Baier G
PKC-theta Modulates the Strength of T Cell Responses by Targeting Cbl-b for Ubiquitination and Degradation.
Science Signal. 2009 Jun 23;2(76):ra30

  Mühlmann G, Spizzo G, Gostner J, Zitt M, Maier H, Moser P, Gastl G, Zitt M, Müller H, Margreiter R, Ofner D, Fong D
TROP2 expression as prognostic marker for gastric carcinoma.
J Clin Pathol. 2009 Feb;62(2):152-8. Epub 2008 Oct

  Fong D, Moser P, Krammel C, Gostner J, Margreiter R, Mitterer M, Gastl G, Spizzo G
High expression of TROP2 correlates with poor prognosis in pancreatic cancer.
Br J Cancer. 2008 Oct 21;99(8):1290-5.

  Fong D, Spizzo G, Gostner J, Gastl G, Moser P, Krammel C, Gerhard S, Rasse M, Laimer K
TROP2: a novel prognostic marker in squamous cell carcinoma of the oral cavity.
Mod Pathol. 2008 Feb;21(2):186-91.

  Laimer K, Spizzo G, Obrist P, Gastl G, Brunhuber T, Schäfer G, Norer B, Rasse M, Haffner M, Doppler W
STAT1 activation in squamous cell cancer of the oral cavity: a potential predictive marker of response to adjuvant chemotherapy.
Cancer, 110(2):326-333.

  Varga M, Obrist P, Schneeberger S, Muhlmann G, Felgel-Farnholz C, Fong D, Zitt M, Brunhuber T, Schafer G, Gastl G, Spizzo G
Overexpression of epithelial cell adhesion molecule antigen in gallbladder carcinoma is an independent marker for poor survival.
Clinical Cancer Research 2004

  Spizzo G, Gastl G, Wolf D, Gunsilius E, Steurer M, Fong D, Amberger A, Margreiter R, Obrist P
Correlation of COX-2 and Ep-CAM overexpression in human invasive breast cancer and its impact on survival.
British Journal of Cancer 2003

  Spizzo G, Obrist P, Went P, Dirnhofer S, Gastl G
Edrecolomab in the adjuvant treatment of colorectal carcinoma.
Lancet 2003

  Spizzo G, Obrist P, Ensinger C, Theurl I, Dunser M, Ramoni A, Gunsilius E, Eibl G, Mikuz G, Gastl G
Prognostic significance of Ep-CAM AND Her-2/neu overexpression in invasive breast cancer.
International Journal of Cancer 2002

  Gastl G, Spizzo G, Obrist P, Dunser M, Mikuz G
Ep-CAM overexpression in breast cancer as predictor of survival.
Lancet 2000