“There won’t be a miracle cure for cancer,” says Thomas Brabletz. “A multi-faceted approach has to be taken to fighting cancer, which means that the most successful treatment strategy is likely to involve an intelligent combination of drugs, often tailored to the individual patient’s needs, that target various weaknesses.” Thomas Brabletz, a renowned cancer researcher, hopes to pinpoint these weaknesses, and is focusing on a relentless opponent that is still almost invariably fatal, even today and in spite of the major advancements made over recent years: metastatic cancer. He is also exploring why some types of cancer develop resistance to treatment and lead to cancer recurring after initially successful treatment.
Thomas Brabletz is Chair of Experimental Medicine I (Molecular Pathogenesis Research) and the Vice Dean for research at the Faculty of Medicine. Ever since he was a student, he has been interested in the biological mechanisms triggering cancer. He chose to focus on molecular pathology and completed his postdoctoral habilitation in this subject at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) in 1998. In 2007, he was appointed professor of molecular oncology at the University of Freiburg, before returning to Erlangen in 2014. Brabletz, who is also a qualified doctor, is one of the leading cancer researchers worldwide; he has published 180 peer reviewed publications and presented his research as a speaker at international conferences and symposia more than 270 times.
Migrating cancer stem cells
Brabletz was the first researcher to identify migrating cancer stem cells as the cause of metastasis and treatment resistance, roughly 20 years ago. “Until then, researchers believed that metastasis was predominantly driven by an irreversible accumulation of mutations,” he explains. Normal stem cells have a decisive role to play in embryonic development and tissue homeostasis. They allow any number of different types of tissues and organs to be formed from an original small cluster of cells. The important factor in this process is that epithelial cells are capable of converting into mesenchymal cells. These mesenchymal cells then migrate to pre-determined locations and develop there into tissue complexes. They are even able to change back into epithelial cells and form compact organs such as the liver or layers lining other organs such as the gut or the lung.
This ability to transform from one type of cell into another, a process that may also occur repeatedly, is known as cell plasticity. “The process more or less stops completely after the embryonic phase,” explains Brabletz. “Unfortunately, it can be reactivated in tumors, and then individual cells can break off from a tumor, migrate throughout the body, and form metastases in far-off organs after converting back into epithelial tumor cells.” This process does not only rely on the cells’ ability to migrate, but also on there being a specific trigger. The research group led by Thomas Brabletz proved in 2017 that aggressive types of tumor such as pancreatic cancer or breast cancer activate a key factor for the embryonic plasticity program, the protein ZEB1. “Pancreatic cancer metastasizes very early on, but often remains undetected until a much later stage,” explains Brabletz. “That is what makes it one of the most challenging and deadly cancers.”
Regulated cell death using ferroptosis
Research funded by the Koselleck program is focusing on investigating these triggers and molecular signal paths. According to Brabletz, “if we succeed in regulating ZEB or similar as yet unknown factors, we may not be able to prevent the initial tumor growth, but we would be able to prevent the formation of metastases. This would significantly improve the survival rate for tumor patients.” However, as it is hard to predict how successful this strategy will be, Brabletz is also focusing on the subsequent processes of ZEB1 activation, for example on rendering existing mobile cancer cells with mesenchymal properties harmless. “One decisive factor is the finding that there are differences between the fatty acid metabolism of epithelial and mesenchymal cells,” the researcher explains. “This means that while epithelial tumor cells react well to chemotherapy and immunotherapy, mesenchymal cancer cells are largely resistant to established methods of treatment. Conversely, there are also processes that have a severe impact on mesenchymal cells but not on epithelial cells.”
One of these processes is known as ferroptosis, a programmed cell death which the body uses to defend itself against malformed cells. As the name suggests, cellular iron plays an important role – in conjunction with fat molecules. “A large quantity of unsaturated fatty acids must be stored in the cell membrane in order to trigger ferroptosis,” explains Brabletz. “Interestingly, that is the case with mesenchymal cell types, whilst epithelial cells remain largely unaffected.” The team led by Thomas Brabletz intends to continue researching the basic mechanisms behind ferroptosis and find potential methods for using them to kill mesenchymal tumor cells. This may involve using the latest technology such as CRISPR/Cas. Brabletz explains, “we want to find out everything about cancer cells, about their molecular structure, their genetic information, their signal pathways. Only then will we be in a position to develop tailored therapies for all forms of cancer.”
About the DFG Reinhart Koselleck funding
Reinhart Koselleck projects give researchers more freedom and scope to work on particularly innovative and promising but higher-risk projects. With this funding, the DFG hopes to give outstanding researchers the possibility to carry out projects such as these. The projects are provided funding of up to 1.25 million euros over a period of five years.