Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis

Nicole Kiweler, Catherine Delbrouck, Vitaly I. Pozdeev, Laura Neises, Leticia Soriano-Baguet, Kim Eiden, Feng Xian, Mohaned Benzarti, Lara Haase, Eric Koncina, Maryse Schmoetten, Christian Jaeger, Muhammad Zaeem Noman, Alexei Vazquez, Bassam Janji, Gunnar Dittmar, Dirk Brenner, Elisabeth Letellier, Johannes Meiser*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

Metastasis is the most common cause of death in cancer patients. Canonical drugs target mainly the proliferative capacity of cancer cells, which leaves slow-proliferating, persistent cancer cells unaffected. Metabolic determinants that contribute to growth-independent functions are still poorly understood. Here we show that antifolate treatment results in an uncoupled and autarkic mitochondrial one-carbon (1C) metabolism during cytosolic 1C metabolism impairment. Interestingly, antifolate dependent growth-arrest does not correlate with decreased migration capacity. Therefore, using methotrexate as a tool compound allows us to disentangle proliferation and migration to profile the metabolic phenotype of migrating cells. We observe that increased serine de novo synthesis (SSP) supports mitochondrial serine catabolism and inhibition of SSP using the competitive PHGDH-inhibitor BI-4916 reduces cancer cell migration. Furthermore, we show that sole inhibition of mitochondrial serine catabolism does not affect primary breast 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.

Original languageEnglish
Article number2699
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 16 May 2022

Keywords

  • Breast Neoplasms/metabolism
  • Carbon Cycle
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Female
  • Folic Acid Antagonists
  • Humans
  • Mitochondria/metabolism
  • Serine/metabolism

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