TY - JOUR
T1 - The gut microbial metabolite formate exacerbates colorectal cancer progression
AU - Ternes, Dominik
AU - Tsenkova, Mina
AU - Pozdeev, Vitaly Igorevich
AU - Meyers, Marianne
AU - Koncina, Eric
AU - Atatri, Sura
AU - Schmitz, Martine
AU - Karta, Jessica
AU - Schmoetten, Maryse
AU - Heinken, Almut
AU - Rodriguez, Fabien
AU - Delbrouck, Catherine
AU - Gaigneaux, Anthoula
AU - Ginolhac, Aurelien
AU - Nguyen, Tam Thuy Dan
AU - Grandmougin, Lea
AU - Frachet-Bour, Audrey
AU - Martin-Gallausiaux, Camille
AU - Pacheco, Maria
AU - Neuberger-Castillo, Lorie
AU - Miranda, Paulo
AU - Zuegel, Nikolaus
AU - Ferrand, Jean Yves
AU - Gantenbein, Manon
AU - Sauter, Thomas
AU - Slade, Daniel Joseph
AU - Thiele, Ines
AU - Meiser, Johannes
AU - Haan, Serge
AU - Wilmes, Paul
AU - Letellier, Elisabeth
N1 - Funding Information:
We thank the patients who kindly donated their samples and made this study possible. We thank members of the Dolznig laboratory (Medical University of Vienna) for the 7TGP-RKO cell line and culturing advice. We also thank D. Kuhn, P. May, C. Martin-Gallausiaux, K. Greenhalgh and T. Bintener for their help. We thank the LCSB Metabolomics Platform, especially C. Jäger, X. Dong and F. Vanhalle, for providing technical and analytical support. We thank all the contributing surgeons and nurses from the Centre Hospitalier Emile Mayrisch, the Centre Hospitalier du Luxembourg, the Zitha Klinic and the Clinical and Epidemiological Investigation Centre of the Luxembourg Institute of Health for their work with the patients. We thank the Fondation Cancer for its support during the setup of the Luxembourgish patients with CRC cohort. We also thank M. Mittelbronn and the pathologists and macroscopy team from NCP/LNS. We also thank their collaborators at the IBBL, F. Betsou, N. Goncharenko, C. Bahlawane and A. Gaignaux for the overall setup of the patient sample collection and the management of the cohort. We are also grateful to D. Coowar for managing the animal facility as well as the veterinarian service (M. Schmit and J. Behm) of the University of Luxembourg for their assistance and guidance in animal welfare during animal experimentation. The experiments presented in this paper were carried out using the high-performance computing facilities at the University of Luxembourg (ref. , https://hpc.uni.lu ). Biorender (BioRender.com) was used for graphical illustration. Funding This work was supported by the Luxembourg National Research Fund (FNR) (grant nos. CORE/C16/BM/11282028 (E.L.), PoC/18/12554295 (E.L.), PRIDE17/11823097 (M.T.), PRIDE19/14254520 (S.A.) and CORE/15/BM/10404093 (P.W.), ATTRACT Programme grant (nos. FNR/A12/01 to I.T. and A18/BM/11809970 to J.M.)), by the Luxembourg National Research Fund and the Fondation Cancer Luxembourg (grant no. CORE/C20/BM/14591557 (E.L.)) as well as by the Fondation du Pélican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg (‘Pelican Grant’; D.T., M.T. and J.K.), a FNRS-Télévie grant to M.M., no. 7.4565.21-40007364), an Internal Research Project at the University of Luxembourg (MiDiCa—integrated analysis of the effects of microbiome-diet interactions on human colorectal adenocarcinoma enterocytes; E.L., P.W., S.H. and D.T.), the Fondation Cancer and the Fondation Kriibskrank Kanner Luxembourg (‘Effects of pesticides on the gut and their role in cancer development, PestGut’, V.I.P and S.H.), the Action LIONS Vaincre le Cancer Luxembourg and a European Research Council grant under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 757922 to I.T. and no. 863664 to P.W.). This project was also supported by the Doctoral School in Science and Engineering (D.T., J.K. and M.T.) and the Department of Life Sciences and Medicine at the University of Luxembourg. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4/18
Y1 - 2022/4/18
N2 - The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium nucleatum, promotes CRC development. We describe molecular signatures linking CRC phenotypes with Fusobacterium abundance. Cocultures of F. nucleatum with patient-derived CRC cells display protumorigenic effects, along with a metabolic shift towards increased formate secretion and cancer glutamine metabolism. We further show that microbiome-derived formate drives CRC tumour invasion by triggering AhR signalling, while increasing cancer stemness. Finally, F. nucleatum or formate treatment in mice leads to increased tumour incidence or size, and Th17 cell expansion, which can favour proinflammatory profiles. Moving beyond observational studies, we identify formate as a gut-derived oncometabolite that is relevant for CRC progression.
AB - The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium nucleatum, promotes CRC development. We describe molecular signatures linking CRC phenotypes with Fusobacterium abundance. Cocultures of F. nucleatum with patient-derived CRC cells display protumorigenic effects, along with a metabolic shift towards increased formate secretion and cancer glutamine metabolism. We further show that microbiome-derived formate drives CRC tumour invasion by triggering AhR signalling, while increasing cancer stemness. Finally, F. nucleatum or formate treatment in mice leads to increased tumour incidence or size, and Th17 cell expansion, which can favour proinflammatory profiles. Moving beyond observational studies, we identify formate as a gut-derived oncometabolite that is relevant for CRC progression.
UR - http://www.scopus.com/inward/record.url?scp=85128389849&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/35437333
U2 - 10.1038/s42255-022-00558-0
DO - 10.1038/s42255-022-00558-0
M3 - Article
C2 - 35437333
AN - SCOPUS:85128389849
SN - 2522-5812
VL - 4
SP - 458
EP - 475
JO - Nature Metabolism
JF - Nature Metabolism
IS - 4
ER -