Our vision is to reach an understanding of cellular metabolism and its regulation that enables us to normalize aberrant disease metabolism by exploiting its naturally embedded control mechanisms. This level of understanding will allow us to design drugs that only target the diseased cells and will yield no side effects on healthy cells. To reach our long-term vision, we reveal functional and mechanistic understanding of cellular metabolism by focusing on metabolic auto-regulation, on the link between cellular metabolism and signaling, and on the regulatory impact of the nutrient environment on cellular metabolism. To gain crucial insights into these research areas we exploit our metabolism expertise, which includes the generation of intracellular metabolism data using steady state 13C tracer infusions to mice, 13C metabolic flux analysis and metabolomics.
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Does the microenvironment shape the metabolism of cancer cells during metastasis formation?
We investigated the role of the microenvironment in shaping cancer metabolism during breast cancer metastasis to the lungs. We discovered that breast cancer-derived lung metastases activate PC-dependent anaplerosis as a function of the nutrient availability within the lung microenvironment. While primary breast cancers often rely on glutamine anaplerosis, the resulting and genetically similar lung metastases activate PC-dependent anaplerosis in response to the lung microenvironment. Thus, we discovered that pyruvate carboxylase-dependent anaplerosis distinguishes lung metastases from their corresponding primary breast cancers. This shows that primary cancer and their resulting metastases can have different metabolic vulnerabilities and consequently should be targeted with different drugs (Christen et al., 2016, Cell Reports).
How can the loss of one and the same enzyme result in two different diseases?
Mutations in succinate dehydrogenase (SDH) are associated with tumor development and neurodegenerative diseases. Only in tumors, loss of SDH activity is accompanied with the loss of complex I activity. Yet, it remains unknown whether the metabolic phenotype of SDH mutant tumors is driven by loss of complex I function, and whether this contributes to the peculiarity of tumor development versus neurodegeneration. We found that sole loss of SDH activity was not sufficient to recapitulate the metabolic phenotype of SDH mutant tumors, because it failed to decrease mitochondrial respiration and to activate reductive glutamine metabolism. These metabolic phenotypes were only induced upon the additional loss of complex I activity. Thus, we show that complex I function defines the metabolic differences between SDH mutation associated tumors and neurodegenerative diseases, which could open novel therapeutic options against both diseases (Lorendeau et al., 2016, Metabolic Engineering).
The latest news can be found below. Interested in more news?
Breast Cancer-Derived Lung Metastases Show Increased Pyruvate Carboxylase-Dependent AnaplerosisChristen S, Lorendeau D, Schmieder R, Broekaert D, Metzger K, Veys K, Elia I, Buescher J, Orth M, Davidson S, Grünewald T, De Bock K, Fendt SCell Reports, 17, 837-848, 2016 Dual loss of succinate dehydrogenase (SDH) and complex I activity is necessary to recapitulate the metabolic phenotype of SDH mutant tumorsLorendeau D, Rinaldi G, Boon R, Spincemaille P, Metzger K, Jäger C, Christen S, Dong X, Kuenen S, Voordeckers K, Verstreken P, Cassiman D, Vermeersch P, Verfaillie C, Hiller K, Fendt SMETABOLIC ENGINEERING, e-pub, e-pub, 2016 Fatty acid carbon is essential for dNTP synthesis in endothelial cellsSchoors S* Brüning U* Missiaen R De Souza Queiroz K Borgers G Elia I Zecchin A Cantelmo A Christen S Goveia J Heggermont W Goddé L Vinckier S Van Veldhoven P Eelen G Schoonjans L Gerhardt H Dewerchin M Baes M De Bock K Ghesquière B Lunt S Fendt S* Carmeliet P*NATURE, 520, 192-7, 2015* These authors contributed equally A roadmap for interpreting C metabolite labeling patterns from cellsBuescher J, Antoniewicz M, Boros L, Burgess S, Brunengraber H, Clish C, Deberardinis R, Feron O, Frezza C, Ghesquière B, Gottlieb E, Hiller K, Jones R, Kamphorst J, Kibbey R, Kimmelman A, Locasale J, Lunt S, Maddocks O, Malloy C, Metallo C, Meuillet E, Munger J, Nöh K, Rabinowitz J, Ralser M, Sauer U, Stephanopoulos G, St-Pierre J, Tennant D, Wittmann C, Vander Heiden M, Vazquez A, Vousden K, Young J, Zamboni N, Fendt SCURRENT OPINION IN BIOTECHNOLOGY, 34C, 189-201, 2015
15/11/2016 - Sarah-Maria Fendt (VIB-KU Leuven): “In this project we have studied mutations in the enzyme succinate dehydrogenase, which are associated with tumors, but also neurodegeneration.
11/10/2016 - Spreading tumor cells are able to adapt their metabolism to the specific organs they are invading. This conclusion forms the gist of a VIB-KU Leuven paper published in the renowned scientific journal Cell Reports.
19/10/2015 - Systems biology provides a unifying framework for biological data collection, analysis and informed intervention. In both biotechnology and biomedicine the ultimate goal is to understand and redirect or repair biological processes.
10/07/2015 - Sandra Schoors, Ulrike Bruning, Sarah-Maria Fendt and Peter Carmeliet (VIB Vesalius Research Center, KU Leuven) have discovered, contrary to all expectations, that fatty acid breakdown is essential for the proliferation of endothelial cells.
01/07/2015 - From September 8 – 10, 2015 VIB will host the interdisciplinary meeting on “Metabolism in Cancer and Stromal Cells” in Leuven.
01/04/2015 - Peter Carmeliet and Sarah-Maria Fendt (VIB/ KU Leuven) have discovered a new strategy to counteract blood vessel formation, based on their research which indicates that fatty acid breakdown is essential in the creation of new blood vessels.
PhD: ETH Zurich, Institute of Molecular Systems Biology, 2009
Postdoctoral Fellow: Harvard Medical School, Boston, 2010
Postdoctoral Fellow: Massachusetts Institute of Technology , Cambridge, 2011-2012
VIB Group leader since 2013