Understanding and targeting the function of formate overflow in cancer cells

Metabolic rewiring is essential during oncogenic transformation. Therefore, targeting this metabolic rewiring holds promise to successfully target cancer.With this application I intend to setup a research group that focuses on cancer metabolism with an emphasis on the role of folate mediated one-carbon(1C) metabolism. Besides its canonical functions to provide intermediates for nucleotide synthesis, I have demonstrated in my previous work, in vitro andin vivo, that 1C metabolism also fulfils a catabolic role, characterised by formate overflow. However, a specific function remains elusive until now. My prediction is that formate overflow affects invasion of cancer cells, which is supported by extensive preliminary data. These data provides evidence that cancer cell invasion increases with increasing formate concentrations and that an inhibition of 1C metabolism results in less invasion. The proposedproject is built on three project arms that together are aimed at understanding the function of formate overflow which in the long term may lead to noveltherapeutic interventions, especially in the context of malignant brain tumors. Moreover, understanding the function and mechanism of formate overflowwill not only have implications in cancer but will also be relevant in the context of other proliferating cells such as immune system related cell types.First, we will validate our preliminary observations in vivo using orthotopic brain tumor models, and we will focus on understanding the underlying mechanism in detail. Second, we will test and characterise the specificity of a novel and promising compound isolated from the myxobacterium Sorangiumcellulosum to inhibit mammalian 1C metabolism. Third, in collaboration with Prof. Rejko Krueger at the LCSB, we will extend the existing automatisation platform by a metabolism screening platform. This platform will allow us to specifically screen for compounds targeting mammalian metabolism.The proposed work includes the use of state-of-the-art mass spectrometry, stable isotope-assisted metabolic flux analysis and clinical relevant in vivobrain tumor models. Overall the proposed research has a clear translational aspect and aims at the identification of novel entry points to target malignanttumors