Increased formate overflow is a hallmark of oxidative cancer

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

doi:10.1038/s41467-018-03777-w

Increased formate overflow is a hallmark of oxidative cancer

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

80 Citations (Scopus)

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.

Original language	English
Article number	1368
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03777-w
Publication status	Published - 1 Dec 2018

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Meiser, J., Schuster, A., Pietzke, M., Voorde, J. V., Athineos, D., Oizel, K., Burgos-Barragan, G., Wit, N., Dhayade, S., Morton, J. P., Dornier, E., Sumpton, D., Mackay, G. M., Blyth, K., Patel, K. J., Niclou, S. P., & Vazquez, A. (2018). Increased formate overflow is a hallmark of oxidative cancer. Nature Communications, 9(1), Article 1368. https://doi.org/10.1038/s41467-018-03777-w

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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.",

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

note = "Funding Information: This work was supported by Cancer Research UK C596/A21140. J.M. was supported by a DFG Fellowship Grant Number: ME 4636/2-1. We acknowledge the Cancer Research UK Glasgow Center (C596/A18076) and the BSU facilities at the Cancer Research UK Beatson Institute (C596/A17196). A.S. was supported by Fondation Cancer Luxembourg (INVGBM project). NCH601 cells were generated in the laboratory of Dr Christel Herold-Mende (Department of Neurosurgery, University of Heidelberg). J.M., A.S. and S.N. thank Vanessa Barthelemy for technical assistance with the shRNA cell lines. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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AU - Burgos-Barragan, Guillermo

AU - Wit, Niek

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AU - Morton, Jennifer P.

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AU - Sumpton, David

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AU - Patel, Ketan J.

AU - Niclou, Simone P.

AU - Vazquez, Alexei

N1 - Funding Information: This work was supported by Cancer Research UK C596/A21140. J.M. was supported by a DFG Fellowship Grant Number: ME 4636/2-1. We acknowledge the Cancer Research UK Glasgow Center (C596/A18076) and the BSU facilities at the Cancer Research UK Beatson Institute (C596/A17196). A.S. was supported by Fondation Cancer Luxembourg (INVGBM project). NCH601 cells were generated in the laboratory of Dr Christel Herold-Mende (Department of Neurosurgery, University of Heidelberg). J.M., A.S. and S.N. thank Vanessa Barthelemy for technical assistance with the shRNA cell lines. Publisher Copyright: © 2018 The Author(s).

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N2 - 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.

AB - 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.

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Increased formate overflow is a hallmark of oxidative cancer

Abstract

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