TY - UNPB
T1 - Formate Promotes Invasion and Metastasis by Activating Fatty Acid Synthesis and Matrix Metalloproteinases
AU - Delbrouck, Catherine
AU - Kiweler, Nicole
AU - Pozdeev, Vitaly I.
AU - Neises, Laura
AU - Oudin, Anaïs
AU - Schuster, Anne
AU - d’Hérouël, Aymeric Fouquier
AU - Shen, Ruolin
AU - Halder, Rashi
AU - Lesur, Antoine
AU - Ogris, Christoph
AU - Lorenz, Nadia I.
AU - Jaeger, Christian
AU - Ronellenfitsch, Michael W.
AU - Piraud, Marie
AU - Skupin, Alexander
AU - Niclou, Simone P.
AU - Letellier, Elisabeth
AU - Meiser, Johannes
N1 - Acknowledgment
We thank Rolf Bjerkvig for providing BG5, BG7, GG6, GG16 GBM cells , Christel Herold-Mende for providing the NCH601 GBM cell line and Clément Thomas (LIH, Luxembourg) for providing 4T1 cells. We would also like to thank Virginie Baus (LIH, Luxembourg) for cutting the mouse brains. We would like to thank: the LCSB Metabolomics Platform, especially Xiangyi Dong and Floriane Vanhalle, for providing technical and analytical support. Also Francois Bernardin for technical asistance with Mass Spec analysis at LIH. We also thank all our
collaboration partners for fruitful discussions and constructive feedback. All graphical figures were produced with BioRender.com. J.M. is supported by the FNR-ATTRACT program (A18/BM/11809970) and CORE program (C21/BM/15718879). N.K. is supported by the LIH Career Launchpad program (Legs Baertz) and by a DFG fellowship (KI 2508/1-1). AS and SPN are grateful for the financial support by Fondation Cancer Luxembourg (INVGBM project)
PY - 2023/1/23
Y1 - 2023/1/23
N2 - 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.
AB - 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.
U2 - 10.1101/2023.01.23.525172
DO - 10.1101/2023.01.23.525172
M3 - Preprint
T3 - bioRxiv
SP - 2023.01.23.525172
BT - Formate Promotes Invasion and Metastasis by Activating Fatty Acid Synthesis and Matrix Metalloproteinases
ER -