Formate Promotes Invasion and Metastasis by Activating MMP2 excretion and Fatty Acid Synthesis
Metabolic rewiring is essential to enable cancer cell proliferation, migration, invasion and metastasis. One important metabolic pathway that is often hijacked by cancer cells is the one-carbon cycle, in which the third carbon atom of serine is oxidized to formate. This metabolic byproduct is essential for nucleotide synthesis in proliferating cells. We have recently uncovered in vitro and in vivo that formate production in cancer cells is often in excess of the anabolic demand. Furthermore, we had indication that high formate concentrations in the extracellular space promote the invasiveness of glioblastoma cells
In the present study, we demonstrate by using ex vivo brain slice cultures and an orthotopic brain tumor model, that silencing MTHFD1L (the gene responsible to synthesize formate) results in decreased invasiveness of glioblastoma (GBM) cells.
Mechanistically, we uncovered that formate promotes excretion of MMP2 and synthesis of fatty acid. Targeting fatty acid synthesis (FAS) in vitro, suppresses the observed formate-dependent pro-invasive effect.
We thus hypothesize that high formate concentrations promote glioblastoma cell invasion by activating lipid metabolism via a yet unknown mechanism.