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

Kiweler, N. et al. (2022) Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis. Nature Communications, 13, 2699. (doi: 10.1038/s41467-022-30363-y) (PMID:35577770) (PMCID:PMC9110368)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Vazquez, Alexei

Creator Roles

Vazquez, A.: Software, Resources, Data curation, Writing – review and editing, Funding acquisition

• Authors: Kiweler, N., Delbrouck, C., Pozdeev, V. I., Neises, L., Soriano-Baguet, L., Eiden, K., Xian, F., Benzarti, M., Haase, L., Koncina, E., Schmoetten, M., Jaeger, C., Noman, M. Z., Vazquez, A., Janji, B., Dittmar, G., Brenner, D., Letellier, E., and Meiser, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Nature Communications 13: 2699
• Publisher Policy: Reproduced under a Creative Commons License