Margareta Wilhelm Group
Mechanisms regulating tumor development and tumor microenvironment
Tumor development is not only dependent on cell intrinsic activation of proliferation and inhibition of senescence and/or apoptosis. It is becoming increasingly clear that tumor initiation, progression, and response to therapy is dependent on a continuous cross talk between tumor cells, the surrounding stroma and infiltrating immune cells. As tumors increase in size the availability of oxygen and nutrients decrease, which leads to metabolic changes and cellular adaptation. Interestingly, it has been shown that it is in the hypoxic areas within tumors the most malignant cells arise. These cells are often resistant to therapy due to intracellular changes as well as being surrounded by a resistant environment. It is important to understand the mechanisms controlling tumor development in order for us to successfully develop therapies against cancer.
The tumor microenvironment creates a permissive niche that allows for tumor growth and spread. The Wilhelm lab is studying both cell intrinsic and extrinsic mechanisms important for tumor progression.
We are specifically interested in how the p73 gene regulates tumor development. p73 belongs to the p53-family of proteins that act as master regulators of cellular life and death decisions and their functions are impaired or altered during tumor development. The p73 gene encodes for full-length proteins that act as transcription factors and tumor suppressors (TAp73) and N-terminally truncated dominant negative isoforms that act as oncogenes (DNp73). We have previously shown that p73 regulates genomic stability, apoptosis, responses to hypoxia, angiogenesis, and drug resistance mechanisms. Building on our findings we are now studying mechanisms important for regulating tumor bioenergetics, tumor-stroma interactions and infiltration of tumor-associated immune cells.
Reprogrammed human stem cells as a model for cancer development
During the past decades, we have seen a virtual explosion in molecularly targeted cancer therapy, with the development of monoclonal antibodies and small molecules targeting specific pathways that have gone awry in cancer cells. However, despite all efforts, targeted cancer therapies have often failed to be effective in large patient populations, with low clinical response rate followed by the emergence of drug resistance. This shows the need for developing new models based on disease-relevant human cells to identify the right biomarkers useful for treatment. Most human cancer cell models used to date are based on immortalized cancer cell lines that poorly reflect the diversity in molecular subclones that exist within each tumor. To overcome this problem, we together with our collaborators, are developing more accurate cancer models that are based on human disease-relevant cells derived by using cellular reprogramming techniques.
Fibroblasts from cancer patients carrying familial cancer predisposition mutations are used for reprogramming into iPS cells and further differentiated into relevant cell type.
The Wilhelm lab is currently recruiting Postdocs, please apply using contact information below. Open positions for Doctoral students are posted on KI homepage when available.
Research group leader Associate Professor Margareta Wilhelm
|Ana Marin Navarro||Anknuten|
|Johanna Wolfsberger||Doktorand, Forskarstuderande|
|Niek van Bree||Anknuten|