2. Academic Validation
  3. Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis

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

  • Nat Commun. 2022 May 16;13(1):2699. doi: 10.1038/s41467-022-30363-y.
Nicole Kiweler 1,  Catherine Delbrouck 1 2,  Vitaly I Pozdeev 3,  Laura Neises 1,  Leticia Soriano-Baguet 2 4 5,  Kim Eiden 1 2,  Feng Xian 6,  Mohaned Benzarti 1 2,  Lara Haase 1 2 7,  Eric Koncina 3,  Maryse Schmoetten 3,  Christian Jaeger 7,  Muhammad Zaeem Noman 8,  Alexei Vazquez 9,  Bassam Janji 8,  Gunnar Dittmar 2 6,  Dirk Brenner 4 5 10,  Elisabeth Letellier 3,  Johannes Meiser 11
Affiliations

Affiliations

  • 1 Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
  • 2 Faculty of Science, Technology and Medicine, University of Luxembourg, 2 avenue de Université, Esch-sur-Alzette, Luxembourg.
  • 3 Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, Molecular Disease Mechanisms Group, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
  • 4 Experimental & Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, 29 Rue Henri Koch, Esch-sur-Alzette, Luxembourg.
  • 5 Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg.
  • 6 Proteomics of cellular signaling, Department of Infection and Immunity, Luxembourg Institute of Health,1a Rue Thomas Edison, Strassen, Luxembourg.
  • 7 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
  • 8 Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
  • 9 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • 10 Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
  • 11 Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg. [email protected].
PMID: 35577770 DOI: 10.1038/s41467-022-30363-y
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.

Figures
Products