Growth Factor Signaling in Cancer Cells
Identification of aberrations in signal transduction pathways involved in cell growth, apoptosis, migration, invasion and angiogenesis has enabled new and improved cancer therapies. Our group focuses on signaling pathways triggered by fibroblast growth factors (FGFs) and activins. The overall aim is, to identify new therapeutic strategies on the basis of increased knowledge about signaling mechanisms driving tumor development and progression.
FGFs and their receptors (FGFR1-4) represent an important signaling axis for cell growth, differentiation and organ development during embryogenesis. Unfortunately, cancer cells can hijack this powerful system for their own benefit and use it for increased proliferation, migration, angiogenesis and invasion into surrounding tissues. In collaboration with the Department of Surgery of the Medical University of Vienna, our group investigates the impact of deregulated FGF signals in malignant pleural mesothelioma (MPM), a very treatment refractory tumor that is mainly caused by exposure to asbestos. We observed that abrogation of FGF-receptor signals by specific inhibitors or genetic constructs can block mesothelioma growth. Importantly, the combination of FGF-receptor inhibitors with ionizing radiation or cisplatin, a chemotherapeutic agent used in the clinic for treatment of MPM, demonstrated synergistic antimesothelioma activity in MPM cell models. In another project we could show in cutaneous melanoma that FGF-receptor inhibitors enhanced and prolonged the response to BRAF inhibitors and delayed development of resistance. In follow up projects we investigate the role of specific FGFs, in particular FGF5 and FGF18.
In order to be able to better dissect the dynamics of signaling mechanisms of FGF-receptors and other receptor tyrosine kinases (RTK), we created light-activated versions of FGFR1, EGFR and RET in collaboration with the Institute of Science and Technology (IST) Austria. In cancer and endothelial cells expressing these Opto-RTKs, signal transduction and cell behavior can be controlled with light and thus investigated with high spatiotemporal precision.
The second family of growth and differentiation factors in the focus of our interest is the activin family. These proteins control differentiation and apoptosis of many cell types and also play a major role in stem cell biology. They can act as tumor supressors in some organs, for instance in the liver, but contribute to tumor aggressiveness in other malignancies including mesothelioma. We aim to understand the different pro- and anti-tumorigenic activities of activin proteins and activin antagonists such as follistatin and Smad7 and explore their potential for therapeutic interference. Current projects investigate the expression patterns and functions of activin A in mesothelioma and other thoracic malignancies.
