Background and goals of our research
Malignant transformation of cells goes along with profound metabolic rewiring to cope with increasing biomass and energy demands. The goal of our research is to understand these metabolic changes pinpointing metabolic bottlenecks that are specific to cancer cells and, ultimately, might become effective targets for clinical oncotherapy.
To evaluate the importance of specific metabolic reactions, it is often not sufficient to measure sole pathway activity but to attain also its quantitative stoichiometry. This quantitative dimension enables to view metabolic fluxes in context and thereby allows an estimate about the importance of a particular pathway in light of cell integrity.
In our lab, we pursue this strategy towards two ends: On one hand, our research efforts aim to target proliferation at the cancer cell’s increased biomass demand, on the other hand, we also try to understand the metabolic processes that allow cell motility and invasion, a key process that is essential for metastasis.
Metastasis is accountable for 90 % of all cancer deaths. Yet, it remains one of the biggest challenges in cancer therapy and is currently seen as incurable.
Until manifestation of metastasis, cancer cells need to cope with very different microenvironments (e.g. pH, O2and nutrient supply, different cell types). In contrast to proliferative cells of the primary tumor, cells that give rise to metastasis are less proliferative and need to cope rather with catabolic determinants to survive in unfavorable conditions. Understanding the (metabolic) survival strategies of cancer cells that escape from the primary tumor to form metastases can reveal novel treatment strategies reducing metastatic burden.
Our own previous work provides one example on how metabolism can influence cell motility and invasion, referring to a phenomenon that we call “formate overflow”. Formate overflow describes a catabolic state in which the amino acid serine is fully catabolized and excreted from cancer cells in form of glycine and formate along with production of reducing equivalents and ATP (without gaining biomass; Meiser et al., 2016. Science Advances). After identifying the existence of this metabolic pathway in vitro and in vivo, we could provide first results indicating that high formate levels promote the invasiveness of glioblastoma cells (Meiser et al., 2018. Nature Communications).
An additional area of interest is the question of how cancer cells interact with their tumor environment. Here, we currently focus our work on immune cells (especially macrophages) as they play an important role in shaping either a tumor promotive or destructive environment. Since, metabolism plays an important role during immune cell activation we try to understand these metabolic dependencies and seek for alternative immune cell-dependent entry points to target cancer cells.