Formate Promotes Invasion and Metastasis by Activating Fatty Acid Synthesis and Matrix Metalloproteinases

Catherine Delbrouck, Nicole Kiweler, Vitaly I. Pozdeev, Laura Neises, Anaïs Oudin, Anne Schuster, Aymeric Fouquier d’Hérouël, Ruolin Shen, Rashi Halder, Antoine Lesur, Christoph Ogris, Nadia I. Lorenz, Christian Jaeger, Michael W. Ronellenfitsch, Marie Piraud, Alexander Skupin, Simone P. Niclou, Elisabeth Letellier, Johannes Meiser*

*Corresponding author for this work

Research output: Working paperPreprint


Metabolic rewiring is essential to enable cancer onset and progression. One important metabolic pathway that is often hijacked by cancer cells is the one-carbon cycle, in which the third carbon of serine is oxidized to formate. We have previously shown that formate production in cancer cells often exceeds the anabolic demand, resulting in formate overflow. Furthermore, we observed that high extracellular formate promotes the in vitro invasiveness of glioblastoma (GBM) cells. However, additional data supporting this in vitro observation and mechanistic details remained elusive so far.In the present study, we now demonstrate that inhibition of formate overflow results in a decreased invasiveness of GBM cells ex vivo and in vivo. Additionally, we observed that exposure to exogeneous formate can induce a transiently stable pro-invasive phenotype that results in increased metastasis formation in vivo. All in all, these results suggest that a local formate increase within the tumor microenvironment may be one factor that can promote cancer cell motility and dissemination.Mechanistically, we uncover a previously undescribed interplay where formate acts as a trigger to alter fatty acid metabolism and matrix metalloproteinase (MMP) activity which in turn impacts cancer cell invasiveness. We thus highlight the role of formate as a pro-invasive metabolite. Gaining a deeper understanding of formate overflow and how it promotes invasion in cancer, may open new therapeutic opportunities to prevent cancer cell dissmination.Competing Interest StatementThe authors have declared no competing interest.
Original languageEnglish
Publication statusPublished - 23 Jan 2023

Publication series

PublisherCold Spring Harbor Laboratory Press


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