Mitochondria are the power houses of the cell, involved in energy production and many other cellular functions. Mitochondria in cancer cells are often less functional compared to normal cells. Cancer cells can compensate for this drawback as they often rely on glycolysis for energy production even under oxygenated conditions which is independent of mitochondria. This phenomenon was discovered in the 1920s by Otto Warburg and is called the Warburg effect. However, recent research has shown that cancer cells can also use oxidative metabolism which is dependent on mitochondria. Our hypothesis is that mitochondria can be transferred from normal surrounding cells in the tumor microenvironment to tumor cells to provide them with metabolic flexibility. In this project, we will investigate the transfer of mitochondria from normal cells to tumor cells and the functional consequences of this transfer for metabolism, tumor growth and invasion. We are focusing on brain tumors, in particular glioblastoma, which is the most malignant and most frequent primary brain tumor. We will define the mechanism of mitochondria transfer and in particular investigate the possible transfer through microtubes, which are connections between tumor cells, but also between tumor and normal cells. Another possible mechanism is the transfer through so-called extracellular vesicles, which are secreted by normal and tumor cells and may contain mitochondria. To identify mechanisms of mitochondria uptake by tumor cells, we will use a genetic screening method. New insights into the mechnanisms of mitochondria transfer could in the future result in the development of new treatment strategies against brain tumors.
Aerobic glycolysis in general has been thought to be a major energy source for cancer cells to grow, invade tissue and metastasize. However, we and others have shown that malignant brain tumor cells can also use mitochondrial respiration to grow and invade, which means that not all mitochondria in tumor cells are dysfunctional or damaged. In particular in invasive tumor areas, where tumor cells interact with normal brain cells, mitochondria transfer from normal cells to cancer cells could equip cancer cells with intact mitochondria and thereby influence metabolism. In preliminary experiments, we were able to show for the first time that mitochondria are transferred from astrocytes to brain tumor cells in vitro, and we are the first group to show mitochondria transfer in vivo (unpublished observations).
The overall aim of this project is to gain new basic understanding of mitochondria transfer between stromal and cancer cells and how this shapes tumor metabolism, invasion and treatment resistance. In this project, we will analyze the mechanism of mitochondria transfer with a special focus on communication structures such as microvesicles and microtubes. Then, we will in detail analyze the metabolism of tumor cells that received mitochondria from stromal cells and we will analyze the metabolic contents of microvesicles. We will define the extent of mitochondria transfer under different stress/therapeutic conditions. Finally, we will identify crucial genes involved in the process of mitochondria transfer which could be potential therapeutic targets. The results of this project will substantially contribute to new knowledge in cancer biology and metabolism and may also open up new treatment avenues for brain cancer treatment.