ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis

• Published in: Cell reports (Cambridge) 2023-06, Vol.42 (6), p.112562-112562, Article 112562
• Main Authors: Hennequart, Marc, Pilley, Steven E., Labuschagne, Christiaan F., Coomes, Jack, Mervant, Loic, Driscoll, Paul C., Legrave, Nathalie M., Lee, Younghwan, Kreuzaler, Peter, Macintyre, Benedict, Panina, Yulia, Blagih, Julianna, Stevenson, David, Strathdee, Douglas, Schneider-Luftman, Deborah, Grönroos, Eva, Cheung, Eric C., Yuneva, Mariia, Swanton, Charles, Vousden, Karen H.
• Format: Article
• Language: English
• Subjects: ALDH1L2; breast cancer; formate; formyl-methionine; metastasis; one-carbon metabolism; ROS; serine
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112562

Mitochondrial 10-formyltetrahydrofolate (10-formyl-THF) is utilized by three mitochondrial enzymes to produce formate for nucleotide synthesis, NADPH for antioxidant defense, and formyl-methionine (fMet) to initiate mitochondrial mRNA translation. One of these enzymes—aldehyde dehydrogenase 1 family member 2 (ALDH1L2)—produces NADPH by catabolizing 10-formyl-THF into CO2 and THF. Using breast cancer cell lines, we show that reduction of ALDH1L2 expression increases ROS levels and the production of both formate and fMet. Both depletion of ALDH1L2 and direct exposure to formate result in enhanced cancer cell migration that is dependent on the expression of the formyl-peptide receptor (FPR). In various tumor models, increased ALDH1L2 expression lowers formate and fMet accumulation and limits metastatic capacity, while human breast cancer samples show a consistent reduction of ALDH1L2 expression in metastases. Together, our data suggest that loss of ALDH1L2 can support metastatic progression by promoting formate and fMet production, resulting in enhanced FPR-dependent signaling. [Display omitted] •Loss of ALDH1L2 increases formate and formyl-methionine production•ALDH1L2 levels influence migration in a formyl-peptide receptor-dependent manner•In the primary tumor, ALDH1L2 levels impact metastatic capacity Hennequart et al. describe the role of ALDH1L2, a mitochondrial enzyme involved in one-carbon metabolism, in breast cancer cells. Loss of ALDH1L2 leads to increased production of formate and formyl-methionine, promoting an increase in migration that is dependent on the formyl-peptide receptor and enhancing metastasis in vivo.