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

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 C. Cheung; Mariia Yuneva; Charles Swanton; Karen H. Vousden

doi:10.1016/j.celrep.2023.112562

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

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 C. Cheung, Mariia Yuneva, Charles Swanton, Karen H. Vousden

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Abstract

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.

Original language	English
Article number	112562
Journal	Cell Reports
Volume	42
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2023.112562
Publication status	Published - 27 Jun 2023
Externally published	Yes

Keywords

ALDH1L2
breast cancer
CP: Cancer
CP: Metabolism
formate
formyl-methionine
metastasis
one-carbon metabolism
ROS
serine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2023.112562

PIIS2211124723005739Final published version, 5.79 MBLicence: CC BY

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Hennequart, M., Pilley, S. E., Labuschagne, C. F., Coomes, J., Mervant, L., Driscoll, P. C., Legrave, N. M., Lee, Y., Kreuzaler, P., Macintyre, B., Panina, Y., Blagih, J., Stevenson, D., Strathdee, D., Schneider-Luftman, D., Grönroos, E., Cheung, E. C., Yuneva, M., Swanton, C., & Vousden, K. H. (2023). ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis. Cell Reports, 42(6), Article 112562. https://doi.org/10.1016/j.celrep.2023.112562

@article{1924219475a84105bcf4daf65e4c5715,

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

abstract = "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.",

keywords = "ALDH1L2, breast cancer, CP: Cancer, CP: Metabolism, formate, formyl-methionine, metastasis, one-carbon metabolism, ROS, serine",

author = "Marc Hennequart and Pilley, {Steven E.} and Labuschagne, {Christiaan F.} and Jack Coomes and Loic Mervant and Driscoll, {Paul C.} and Legrave, {Nathalie M.} and Younghwan Lee and Peter Kreuzaler and Benedict Macintyre and Yulia Panina and Julianna Blagih and David Stevenson and Douglas Strathdee and Deborah Schneider-Luftman and Eva Gr{\"o}nroos and Cheung, {Eric C.} and Mariia Yuneva and Charles Swanton and Vousden, {Karen H.}",

note = "Funding Information: The authors would like to thank the following: Prof. Joshua Rabinowitz for sharing his liquid chromatography-mass spectrometry (LC-MS) derivatization protocol for formate detection, Prof. Stamp for evaluating the histopathology of mouse models, the Crick BRF for helping with the animal experiments, and the Crick flow cytometry facility for helping with sorting and flow cytometry experiments. Metabolomic analysis was supported by Dr. James Macrae and the metabolomics STP of the Francis Crick Institute and through provision of access to the MRC Biomedical NMR Centre . The work was funded by Cancer Research UK grant C596/A26855 and supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( CC2073 ), the UK Medical Research Council ( CC2073 ), and the Wellcome Trust ( CC2073 ). J.B. is funded by the Kuok Family Fellowship . C.S. is a Royal Society Napier Research Professor ( RSRP∖R∖210001 ). His work is supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( CC2041 ), the UK Medical Research Council ( CC2041 ), and the Wellcome Trust ( CC2041 ). C.S. and E.G. are supported by an ERC Advanced Grant ( PROTEUS , grant agreement no. 835297 ). M.Y. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK ( CC2082 ), the UK Medical Research Council ( CC2082 ), and the Wellcome Trust ( CC2082 ). For the purpose of open access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = jun,

day = "27",

doi = "10.1016/j.celrep.2023.112562",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "6",

}

Hennequart, M, Pilley, SE, Labuschagne, CF, Coomes, J, Mervant, L, Driscoll, PC, Legrave, NM, Lee, Y, Kreuzaler, P, Macintyre, B, Panina, Y, Blagih, J, Stevenson, D, Strathdee, D, Schneider-Luftman, D, Grönroos, E, Cheung, EC, Yuneva, M, Swanton, C & Vousden, KH 2023, 'ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis', Cell Reports, vol. 42, no. 6, 112562. https://doi.org/10.1016/j.celrep.2023.112562

TY - JOUR

T1 - ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis

AU - Hennequart, Marc

AU - Pilley, Steven E.

AU - Labuschagne, Christiaan F.

AU - Coomes, Jack

AU - Mervant, Loic

AU - Driscoll, Paul C.

AU - Legrave, Nathalie M.

AU - Lee, Younghwan

AU - Kreuzaler, Peter

AU - Macintyre, Benedict

AU - Panina, Yulia

AU - Blagih, Julianna

AU - Stevenson, David

AU - Strathdee, Douglas

AU - Schneider-Luftman, Deborah

AU - Grönroos, Eva

AU - Cheung, Eric C.

AU - Yuneva, Mariia

AU - Swanton, Charles

AU - Vousden, Karen H.

N1 - Funding Information: The authors would like to thank the following: Prof. Joshua Rabinowitz for sharing his liquid chromatography-mass spectrometry (LC-MS) derivatization protocol for formate detection, Prof. Stamp for evaluating the histopathology of mouse models, the Crick BRF for helping with the animal experiments, and the Crick flow cytometry facility for helping with sorting and flow cytometry experiments. Metabolomic analysis was supported by Dr. James Macrae and the metabolomics STP of the Francis Crick Institute and through provision of access to the MRC Biomedical NMR Centre . The work was funded by Cancer Research UK grant C596/A26855 and supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( CC2073 ), the UK Medical Research Council ( CC2073 ), and the Wellcome Trust ( CC2073 ). J.B. is funded by the Kuok Family Fellowship . C.S. is a Royal Society Napier Research Professor ( RSRP∖R∖210001 ). His work is supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( CC2041 ), the UK Medical Research Council ( CC2041 ), and the Wellcome Trust ( CC2041 ). C.S. and E.G. are supported by an ERC Advanced Grant ( PROTEUS , grant agreement no. 835297 ). M.Y. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK ( CC2082 ), the UK Medical Research Council ( CC2082 ), and the Wellcome Trust ( CC2082 ). For the purpose of open access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. Publisher Copyright: © 2023 The Author(s)

PY - 2023/6/27

Y1 - 2023/6/27

N2 - 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.

AB - 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.

KW - ALDH1L2

KW - breast cancer

KW - CP: Cancer

KW - CP: Metabolism

KW - formate

KW - formyl-methionine

KW - metastasis

KW - one-carbon metabolism

KW - ROS

KW - serine

UR - http://www.scopus.com/inward/record.url?scp=85160284786&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.112562

DO - 10.1016/j.celrep.2023.112562

M3 - Article

C2 - 37245210

AN - SCOPUS:85160284786

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 112562

ER -

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

Abstract

Keywords

UN SDGs

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Francis Crick Institute Reports Findings in Cancer (ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis)

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

Abstract

Keywords

UN SDGs

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Francis Crick Institute Reports Findings in Cancer (ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis)

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