(Vienna, 01 February 2019) Hepatocellular carcinoma (HCC) is one of the commonest and most aggressive forms of liver cancer. The Axl receptor is a key factor in the development and progression of this type of malignant tumour. If the protein Gas6 binds to Axl, the latter is activated, initiating the signal transduction that drives the progression of HCC. In many cases, the part of the receptor located on the surface of the cell (extracellular domain) cleaves off from the cell. In the funded project, Wolfgang Mikulits, from MedUni Vienna's Institute of Cancer Research and member of the Comprehensive Cancer Center (CCC) of MedUni Vienna/Vienna General Hospital, and his team are investigating what influence cleavage of the Axl receptor has on HCC progression and metastasis and on the development of chronic liver disease (CLD).
The binding of Gas6 to Axl triggers the invasion of liver tumour cells, which is a central part of metastasis. But even if the extracellular domain of Axl cleaves off, the part of the receptor that remains in the cell membrane continues to send signals into the cell interior.
As part of the FWF-funded project, Mikulits and his team are now investigating what role the proteins Gas6 and Axl play in signal transduction. That is to say, whether the signals that are transmitted are dependent upon Gas6, as is the case with the intact Axl receptor, or whether transduction also occurs independently of Gas6, as in cleavage of the extracellular domain, in which Gas6 it is also separated.
They are also investigating whether cleavage leads to modified gene expression. That is to say, the researchers are comparing this gene expression with that which occurs when there is no cleavage of the extracellular domain. The aim is to apply these findings therapeutically.
In precisely this context, the researchers want to use complex cell models to test a large number of small molecules in high-throughput screening, to see whether they could have a therapeutic effect on HCC.
Says Mikulits: "We want our project to produce new insights into cleavage of the Axl receptor. In future, these could be used in the development of innovative personalised strategies for effectively combating hepatocellular carcinoma – and even other diseases such as fibrosis of the liver."
Total funding for the individual FWF project is €408,936 and this will be paid by the Herzfelder Family Foundation for the next 3.5 years.
About Wolfgang Mikulits
Wolfgang Mikulits is a research group leader and head of “Tumour Progression and Metastasis" research at the Institute of Cancer Research. His scientific focus includes research into the molecular mechanisms of hepatocellular carcinoma development and metastatic dissemination. This research grant will make it possible to gain new insights into the pathobiology of the Axl receptor, which can then be used in future for personalised strategies for effectively combating liver cancer.
About the FWF
The FWF (Austrian Science Fund) is Austria's central institution for funding basic research. It's purpose is to promote ongoing development of top-level science, thereby enhancing Austria's position as a scientific location.