Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis

Kiweler, N.; Delbrouck, C.; Neises, L.; Pozdeev, V. I.; Soriano-Baguet, L.; Xian, F.; Benzarti, M.; Haase, L.; Schmoetten, M.; Jaeger, C.; Noman, M. Z.; Vazquez, A.; Janji, B.; Dittmar, G.; Brenner, D.; Letellier, E.; Meiser, J.

doi:10.1101/2021.05.27.445928

bioRxiv · 10.1101/2021.05.27.445928

Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis

Kiweler, N.·Delbrouck, C.·Neises, L.·Pozdeev, V. I.·Soriano-Baguet, L.·Xian, F.·Benzarti, M.·Haase, L.·Schmoetten, M.·Jaeger, C.·Noman, M. Z.·Vazquez, A.·Janji, B.·Dittmar, G.·Brenner, D.·Letellier, E.·Meiser, J.

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Abstract

Progression of primary cancer to metastatic disease is the most common cause of death in cancer patients with minimal treatment options available. Canonical drugs target mainly the proliferative capacity of cancer cells, which often leaves slow-proliferating, persistent cancer cells unaffected. Metabolic determinants that contribute to growth-independent functions supporting resistance and metastatic dissemination are still poorly understood. In the present study, we revealed that antifolate treatment results in an uncoupled and autarkic mitochondrial one-carbon (1C) metabolism allowing sustained serine catabolism and formate overflow when cytosolic 1C metabolism is impaired. Interestingly, antifolate dependent growth-arrest did not correlate with decreased migration capacity. Therefore, using the antifolate Methotrexate as a tool compound allowed us to disentangle proliferation and migration to profile the metabolic phenotype of migrating (growth-arrested) cells. Supported by an increased NAD/NADH ratio, we observed increased serine de novo synthesis and increased serine catabolism to formate. Consequently, inhibition of serine de novo synthesis using the competitive PHGDH-inhibitor BI-4916 or direct inhibition of mitochondrial 1C metabolism reduced cancer cell migration. Using an orthotopic breast cancer model, we show that sole inhibition of mitochondrial serine catabolism does not affect primary tumor growth but strongly inhibits pulmonary metastasis. We conclude that mitochondrial 1C metabolism, despite being dispensable for proliferative capacities, confers an advantage to cancer cells by supporting their motility potential. Our results improve our understanding of 1C metabolism and of metabolic determinants that support the process of cancer cell migration and metastasis.

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Kiweler, N., Delbrouck, C., Neises, L., Pozdeev, V. I., Soriano-Baguet, L., Xian, F., Benzarti, M., Haase, L., Schmoetten, M., Jaeger, C., Noman, M. Z., Vazquez, A., Janji, B., Dittmar, G., Brenner, D., Letellier, E., Meiser, J.. 2021-05-27. Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis. https://doi.org/10.1101/2021.05.27.445928

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