Medical University of Vienna
Institute for Cancer Research
Head of Tumor Progression and Metastasis
Department of Medicine I
1090 Vienna, Austria
Phone: +43 1 40160-57527
Fax: +43 1 40160-957519
The development of carcinomas is a multistep process which most frequently leads to the metastatic dissemination of primary tumors. The escape of cancerous cells from the solid tumor is mostly associated with epithelial dedifferentiation and includes phenotypical conversions of cancer cells by changes in epithelial plasticity. We focus on the molecular mechanisms of the epithelial to mesenchymal transition (EMT) and its reversal MET which is of outmost relevance for progression and metastatic colonization of hepatocellular carcinoma (HCC). We particularly address the question how these mechanisms of EMT can be exploited for efficient diagnosis and novel anti-cancer therapy of HCC.
“Role of CXCL5 in the plasticity and progression of hepatocellular carcinoma”
We have shown that TGF-β/Smad signaling suppresses tumorigenesis at early stages but induces EMT and cancer cell invasion at later stages of HCC. As a molecular mechanism underlying this “TGF-β switch”, we recently identified the chemokine CXCL5 as a novel target gene of TGF-β in EMT models of HCC. Notably, CXCL5 is almost exclusively expressed in TGF-β-positive HCC patients, correlating with neutrophil infiltration and poor patient survival. The aim of this project is to discern the role of TGF-β/CXCL5 in regulating cell plasticity, immunophenotype and chemoresistance of HCC cells through its impact on EMT and neutrophil activation. We will perform gain- and loss-of-function studies by genetic and pharmacological intervention in 3-dimensional HCC models to investigate the role of CXCL5 in EMT-MET cycles and chemoresistance. Mouse xenografts and PDX models of HCC will be used to reveal the impact of CXCL5 and neutrophil recruitment on the resistance against sorafenib and regorafenib or chemotherapeutics applied in transendothelial chemoembolization. We will assess the immunophenotype of a large panel of available HCC patient tissues through multiplexed immunohistochemistry of immune cells by multichannel fluorescence imaging combined with tissue Phenomics. The infiltration of T cell subsets will be correlated with the TGF-β/CXCL5-dependent attraction of neutrophils and clinical records of HCC patient samples. This project will link epithelial cell plasticity to immune cell regulation and drug resistance to understand their relevance and interdependence in HCC progression and therapy response.
- Haider, C., Hnat, J., Wagner, R., Huber, H., Timelthaler, G., Grubinger, G., Coulouarn, C., Schreiner, W., Schlangen, K., Sieghart, W., Peck-Radosavljevic, M., and Mikulits, W. (2019) Transforming Growth Factor-β and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma. Hepatology 69: 222-236.
- Dengler, M., Staufer, K., Huber, H., Stauber, R., Bantel, H., Weiss, K.H., Starlinger, P., Pock, H., Klöters-Plachky, P., Gotthardt, D.N., Rauch, P., Lackner, C., Stift, J., Brostjan, C., Gruenberger, T., Kumada, T., Toyoda, H., Tada, T., Weiss, T.S., Trauner, M., and Mikulits, W. (2017) Soluble Axl is an accurate biomarker of cirrhosis and hepatocellular carcinoma development: results from a large scale multicenter analysis. Oncotarget 8: 46234-46248.
- Reichl, P., Dengler, M., van Zijl, F., Huber, H., Führlinger, G., Reichel, C., Sieghart, W., Peck-Radosavljevic, M., Grubinger, M. and Mikulits, W. (2015) Signaling of Axl via 14-3-3zeta Activates Autocrine Transforming Growth Factor-β Signaling in Hepatocellular Carcinoma. Hepatology 61: 930-941.
- Reichl, P., Fang, M., Starlinger, P., Staufer, K., Nenutil, R., Muller, P., Greplova, K., Valik, D., Dooley, S., Brostjan, C., Gruenberger, T., Shen, J., Man, K., Trauner, M., Yu, J., Gao, C.F., and Mikulits, W. (2015) Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma. Int. J. Cancer 137: 385-394.
- Petz, M., Them, N.C.C., Huber, H., and Mikulits, W. (2012) PDGF enhances IRES mediated translation of Laminin B1 by cytoplasmic accumulation of La during epithelial to mesenchymal transition. Nucleic Acids Res. 40: 9738-9749.
- Petz, M., Them, N., Huber, H., Beug, H., and Mikulits, W. (2012) La activates IRES-mediated translation of Laminin B1 during malignant epithelial to mesenchymal transition. Nucleic Acids Res. 40: 290-302.
- Schneller, D., Machat, G., Sousek, A., Proell, V., van Zijl, F., Zulehner, G., Huber, H., Mair, M., Muellner, M.K., Nijman, S.M.B., Eferl, R., Moriggl, R., and Mikulits, W. (2011) p19ARF/p14ARF controls oncogenic functions of Stat3 in hepatocellular carcinoma. Hepatology 54: 164-172.