Submitted Abstract
Metabolic rewiring is essential during oncogenic transformation to meet the increasing biomass and energy demand required for cell duplication. Therefore, targeting this metabolic rewiring holds promise to successfully target cancer. Conclusively, cancer metabolism re-emerged as one of the research hotspots during the last two decades, resulting in clinical trials on the way to improve patient care. With this ATTRACT 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, a pathway essential for life. Besides its canonical anabolic functions to provide intermediates for nucleotide synthesis, I have demonstrated in my previous work, in vitro and in vivo, that 1C metabolism also fulfils a catabolic role, characterised by serine catabolism with formate overflow (excessive formate production that results in formate excretion). However, a specific function for this phenomenon remains elusive until now. My prediction is that formate overflow promotes invasion of cancer cells, which is supported by extensive preliminary data. These data provide evidence that cancer cell invasion increases with increasing formate concentrations and that genetic inhibition of 1C metabolism results in less invasion. The proposed project is built on five project arms that together are aimed at understanding the reason for formate overflow in mammalian cells, and the mechanism that controls formate mediated cell invasion and finding ways to target it for translational application. The generated knowledge will not only have implications in cancer but will also be relevant in the context of other formate overflow positive cell types e.g. cells of the immune system. More specifically, we intend to (i) unravel the underlying mechanism that controls formate mediated cell invasion, (ii) validate our in vitro results with orthotopic brain tumour models in vivo, (iii) investigate the role of serine catabolism with formate overflow during activation of microglia cells (iv) investigate the function of a novel and very potent inhibitor against mammalian methylenetetrahydrofolate dehydrogenase (MTHFD), a key enzyme involved in serine catabolism and (v) in collaboration with the Luxembourg Centre for Systems Biomedicine, establish novel infrastructures to pave the way towards compound screens against metabolic targets.The proposed work includes the use of state-of-the-art mass spectrometry, stable isotope-assisted metabolic flux analysis, clinical relevant in vivo brain tumour models and a novel inhibitor against mammalian 1C metabolism. Overall the proposed research has a clear translational aspect and aims at the identification of novel entry points to target malignant tumours.