Scientists need novel technologies to discover and test oncogenic pathways for different types of cancer. Thanks to high throughput technologies such as “Deep Sequencing” more and more signaling proteins of these pathways can be identified. A crucial limiting factor for understanding the biology of cancers and for developing targeted cancer drugs, however, is the limited knowledge what function the identified signaling proteins have. Quicker and more efficient tools to validate the respective cancer genes on the organismal level are therefore needed.

In this joint funding project is a collaboration of scientists from the DKTK research program “Oncogenic Pathways” and the DKTK research platform “Preclinical Models” located at all partner sites. They aim to establish methods that effectively and reliably inactivate signaling proteins by using high throughput technologies. For that to happen, certain genes are being silenced through molecular-genetic processes such as RNA-interference or CRISPR nucleases. With high throughput technologies hundreds of genes of a certain signaling pathway can be blocked – one gene per petri-dish. If the tumor cells in one petri-dish lose their tumor characteristics, the researchers know that they need to follow up on the relationship between this knocked-out gene or signaling protein and its function. The technology is utilized for different key themes in the research program (cell growth and cell differentiation, tumor microenvironment, apoptosis and epigenetics) as well as various tumor entities. Different two and three dimensional cell cultures as well as mouse tumor models are being used.  

As part of the Joint Funding Project, scientists under guidance of Clemens Schmitt, Berlin, will build up a small RNA-interference library to analyze the regulation of tumor suppressors in lymphomas. Specific signaling proteins shall be identified which could be clinically relevant as pharmacological target structures. Additionally, scientists of the Joint Funding Project guided by Roland Rad and Roland Schmid, both Munich, will develop so-called genome editing technologies. These technologies can specifically turn off the genes belonging to identified signaling proteins in animal models or edit in certain variations. The observed impact on cancer development and metastasizing provide important information on the activity of individual signaling proteins and their suitability in diagnostics and therapy. Scientists headed by Cornelius Miething, Freiburg, will implement an RNA-interference library for key enzymes in cellular signal processing, the so-called kinases (>800 genes), phosphatases (>200 genes), peptidases (>400 genes) as well as peptidase inhibitors (>180 genes). To establish relevant animal models, the project closely collaborates with the Helmholtz-Alliance “Preclinical Comprehensive Cancer Center (PCCC)” which is headed by the Heidelberg DKTK scientist Hellmut Augustin.