[en] 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.
Disciplines :
Oncology
Author, co-author :
MEISER, Johannes ; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Schuster, Anne; Department of Oncology, NorLux Neuro-Oncology Laboratory, Luxembourg Institute of Health, L-1526, Luxembourg, Luxembourg.
Pietzke, Matthias; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Vande Voorde, Johan; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Athineos, Dimitris ; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Oizel, Kristell; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Dhayade, Sandeep; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Morton, Jennifer P; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK. ; Institute for Cancer Sciences, University of Glasgow, G61 1BD, Glasgow, UK.
Dornier, Emmanuel ; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Sumpton, David; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Mackay, Gillian M; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Blyth, Karen ; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Patel, Ketan J; MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK. ; Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 2QQ, UK.
NICLOU, Simone P. ; Department of Oncology, NorLux Neuro-Oncology Laboratory, Luxembourg Institute of Health, L-1526, Luxembourg, Luxembourg. ; Department of Biomedicine, Kristian Gerhard Jebsen Brain Tumour Research Center, University of Bergen, Bergen, N-5009, Norway.
Vazquez, Alexei ; Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK. a.vazquez@beatson.gla.ac.uk. ; Institute for Cancer Sciences, University of Glasgow, G61 1BD, Glasgow, UK. a.vazquez@beatson.gla.ac.uk.
Warburg, O. On the origin of cancer cells. Science 123, 309-314 (1956).
Boland, M. L., Chourasia, A. H. & Macleod, K. F. Mitochondrial dysfunction in cancer. Front. Oncol. 3, 292 (2013).
Marin-Valencia, I. et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell. Metab. 15, 827-837 (2012).
DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).
Garcia-Martinez, L. F. & Appling, D. R. Characterization of the folatedependent mitochondrial oxidation of carbon 3 of serine. Biochemistry 32, 4671-4676 (1993).
Tibbetts, A. S. & Appling, D. R. Compartmentalization of mammalian folatemediated one-carbon metabolism. Annu. Rev. Nutr. 30, 57-81 (2010).
Ducker, G. S. et al. Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway. Cell. Metab. 23, 1140-1153 (2016).
Burgos-Barragan, G. et al. Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism. Nature 548, 549-554 (2017).
Vazquez, A., Markert, E. K. & Oltvai, Z. N. Serine biosynthesis with one carbon catabolism and the glycine cleavage system represents a novel pathway for ATP generation. PLoS One 6, e25881 (2011).
Meiser, J. et al. Serine one-carbon catabolism with formate overflow. Sci. Adv. 2, e1601273 (2016).
Bao, X. R. et al. Mitochondrial dysfunction remodels one-carbon metabolism in human cells. eLife 5, e10575 (2016).
Tumanov, S., Bulusu, V., Gottlieb, E. & Kamphorst, J. J. A rapid method for quantifying free and bound acetate based on alkylation and GC-MS analysis. Cancer Metab. 4, 17 (2016).
Dorokhov, Y. L., Shindyapina, A. V., Sheshukova, E. V. & Komarova, T. V. Metabolic methanol: molecular pathways and physiological roles. Physiol. Rev. 95, 603-644 (2015).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011).
Bougnaud, S. et al. Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma. Oncotarget 7, 31955-31971 (2016).
Lopez-Jimenez, E. et al. Research resource: transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol. Endocrinol. 24, 2382-2391 (2010).
Locasale, J. W. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13, 572-583 (2013).
Ducker, G. S. & Rabinowitz, J. D. One-carbon metabolism in health and disease. Cell. Metab. 25, 27-42 (2017).
Lehtinen, L. et al. High-throughput RNAi screening for novel modulators of vimentin expression identifies MTHFD2 as a regulator of breast cancer cell migration and invasion. Oncotarget 4, 48-63 (2013).
Koufaris, C. et al. Suppression of MTHFD2 in MCF-7 breast cancer cells increases glycolysis, dependency on exogenous glycine, and sensitivity to folate depletion. J. Proteome Res. 15, 2618-2625 (2016).
Di Pietro, E., Sirois, J., Tremblay, M. L. & MacKenzie, R. E. Mitochondrial NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase is essential for embryonic development. Mol. Cell. Biol. 22, 4158-4166 (2002).
Momb, J. et al. Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice. Proc. Natl Acad. Sci. USA 110, 549-554 (2013).
Campos, B. et al. Differentiation therapy exerts antitumor effects on stem-like glioma cells. Clin. Cancer Res. 16, 2715-2728 (2010).
Tedeschi, P. M. et al. Quantification of folate metabolism using transient metabolic flux analysis. Cancer Metab. 3, 6 (2015).
Moser, A. R., Pitot, H. C. & Dove, W. F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322-324 (1990).
Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954-961 (1992).
Adams, J. M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533-538 (1985).
Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 7, 469-483 (2005).
Mackay, G. M., Zheng, L., van den Broek, N. J. & Gottlieb, E. Analysis of cell metabolism using LC-MS and isotope tracers. Methods Enzymol. 561, 171-196 (2015).
