Increased formate overflow is a hallmark of oxidative cancer

Johannes Meiser,Alexei Vazquez,Sandeep Dhayade,Kristell Oizel,Johan Vande Voorde,Guillermo Burgos-Barragan,Karen Blyth,Ketan J Patel,Simone P Niclou,David Sumpton,Dimitris Athineos,Niek Wit,Anne Schuster,Matthias Pietzke,Emmanuel Dornier,Jennifer P Morton,Gillian M Mackay

doi:10.1038/s41467-018-03777-w

Abstract

Formate overflow coupled to mitochondrial oxidative metabolism\\ has been observed in cancer cell lines, but whether that takes place in the tumor microenvironment is not known. Here we report the observation of serine catabolism to formate in normal murine tissues, with a relative rate correlating with serine levels and the tissue oxidative state. Yet, serine catabolism to formate is increased in the transformed tissue of in vivo models of intestinal adenomas and mammary carcinomas. The increased serine catabolism to formate is associated with increased serum formate levels. Finally, we show that inhibition of formate production by genetic interference reduces cancer cell invasion and this phenotype can be rescued by exogenous formate. We conclude that increased formate overflow is a hallmark of oxidative cancers and that high formate levels promote invasion via a yet unknown mechanism.

Highlights

Formate overflow coupled to mitochondrial oxidative metabolism\ has been observed in cancer cell lines, but whether that takes place in the tumor microenvironment is not known
Using the 13C–MeOH tracing protocol we developed an in vivo metabolic flux analysis to determine the relative rate of serine catabolism to formate (SCF) (Fig. 3a)
We determined that the relative rate of serine catabolism to formate is increased in the analyzed transformed tissues relative to adjacent normal tissues and is the highest among all tissues analyzed

Summary

Results

Formate overflow is controlled by the redox state in vitro. In vitro studies indicate that formate release requires active mitochondrial oxidative phosphorylation[5, 10, 11]. The fraction of de novo synthesized purines was higher in the spleen than in the brain, the opposite of what we determined for the relative rate of serine catabolism to formate (SCF, Fig. 3e) Taken together these data indicate that in vivo serine catabolism to formate is associated with serine levels and the tissue redox state, but is not correlated with the rate of purine synthesis. When combined together to calculate the SCI, the adenomas exhibit the highest value, significantly higher than in the adjacent non-transformed small intestine tissue (p = 0.004, unpaired t-test) (Fig. 4c) These findings indicate a high tumor-specific potential for serine catabolism to formate. We deployed the 13C–MeOH tracing protocol to quantify the rate of serine catabolism to formate and to test whether it is increased in the adenomas of APCMin/+ mice relative to normal adjacent tissue. As a second independent model, we have investigated the PyMT

H C OH H

Discussion

Methods