The Francis Crick Institute
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ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis.

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journal contribution
posted on 2023-05-30, 14:01 authored by Marc Hennequart, Steven E Pilley, Christiaan F Labuschagne, Jack Coomes, Loic Mervant, Paul C Driscoll, Nathalie M Legrave, Younghwan Lee, Peter Kreuzaler, Benedict Macintyre, Yulia Panina, Julianna Blagih, David Stevenson, Douglas Strathdee, Deborah Schneider-Luftman, Eva Grönroos, Eric Cheung, Mariia Yuneva, Charles Swanton, Karen H Vousden
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.


Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics) Crick (Grant ID: CC1067, Grant title: STP Metabolomics) Crick (Grant ID: CC2041, Grant title: Swanton CC2041) Crick (Grant ID: CC2073, Grant title: Vousden CC2073) Crick (Grant ID: CC2082, Grant title: Yuneva CC2082) Cancer Research UK (Grant ID: 26855, Grant title: CRUK C596/A26855) European Research Council (Grant ID: 835297 - PROTEUS, Grant title: ERC 835297 - PROTEUS)