Elucidating the role of formate on cancer cell invasion

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 (1C) cycle, in which the third carbon of serine is oxidized to formate. It was previously shown that formate production in cancer cells often exceeds the anabolic demand, resulting in formate overflow. Furthermore, extracellular formate was described to promote the in vitro invasiveness of glioblastoma (GBM) cells. Nevertheless, the mechanism underlying the formate-induced invasion remains elusive.
In this present study, we aimed to characterize formate-induced invasion in greater detail. At first, we studied the generalizability of formate-induced invasion in different GBM models as well as in different breast cancer models. We applied different in vitro assays, like the Boyden chamber assay to probe the impact of formate on different cancer cell lines. Then, we studied the in vivo relevance and the pro-invasive properties of formate in physiological models by using different ex vivo and in vivo models. Lastly, we investigated the mechanism underlying the formate-dependent pro-invasive phenotype. We applied a variety of different biochemical as well as cellular assays to investigate the underlying mechanism.
In the present study, we underline that formate specifically promotes invasion and not migration in different cancer types. Furthermore, we now demonstrate that inhibition of formate overflow results in a decreased invasiveness of GBM cells ex vivo and in vivo. Using breast cancer models, we also obtain first evidence that formate does not only promote local cancer cell invasion but also metastasis formation in vivo, suggesting that locally increased formate concentrations within the tumour microenvironment promote cancer cell motility and dissemination.
Mechanistically, we uncover a previously undescribed interplay where formate acts as a trigger to alter fatty acid metabolism, which in turn affects cancer cell invasiveness and metastatic potential via matrix metalloproteinase (MMP) release.
Gaining a better mechanistic understanding of formate overflow, and how formate promotes invasion in cancer, may contribute to preventing cancer cell dissemination, one of the main reasons for cancer-related mortality.