[en] Gut microbial species contribute to colorectal cancer (CRC) by interacting with tumor or immune cells, however if CRC-associated bacteria engage with stromal components of the tumor microenvironment remains unclear. Here, we report interaction between the CRC-associated bacterium Fusobacterium nucleatum and cancer-associated fibroblasts (CAFs), and show that F. nucleatum is present in the stromal compartment in murine CRC models in vivo and can attach to and invade CAFs. F. nucleatum-exposed CAFs exhibit a pronounced inflammatory-CAF (iCAF) phenotype, marked by elevated expression of established iCAF markers, secretion of pro-inflammatory cytokines such as CXCL1, IL-6 and IL-8, generation of reactive oxygen species (ROS), and an increased metabolic activity. In co-culture experiments, the interaction of cancer cells with F. nucleatum-stimulated CAFs enhances invasion, a finding further validated in vivo. Altogether, our results point to a role for the tumor microbiome in CRC progression by remodeling the tumor microenvironment through its influence on cancer-associated fibroblasts, suggesting novel therapeutic strategies for targeting CRC.
Disciplines :
Microbiology
Author, co-author :
KARTA, Jessica ✱; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
MEYERS, Marianne ✱; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
RODRIGUEZ, Fabien ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
KONCINA, Eric ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
PEREZ ESCRIVA, Pau ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
MOLINA TIJERAS, Jose Alberto ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
CORREIA TAVARES BERNARDINO, Catarina ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Ponath, Falk; Institute of Molecular Infection Biology, University of Würzburg, Würzburg, Germany
Carpentier, Anais; Laboratoire National de Santé (LNS), National Center of Pathology (NCP), Dudelange, Luxembourg
Pujabet, Mònica Aguilera; Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain
SCHMOETTEN, Maryse ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
TSENKOVA, Mina ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
SAOUD, Perla ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
GAIGNEAUX, Anthoula ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
TERNES, Dominik ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
Alonso, Lidia; Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain
Zügel, Nikolaus; Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg
Willemssen, Eric; Groupe Chirurgical Zitha, Hôpitaux Robert Schuman, Luxembourg, Luxembourg
Koppes, Philippe; Groupe Chirurgical Zitha, Hôpitaux Robert Schuman, Luxembourg, Luxembourg
Léonard, Daniel ; Groupe Chirurgical Zitha, Hôpitaux Robert Schuman, Luxembourg, Luxembourg
Casanova, Luis Perez; Laboratoire National de Santé (LNS), National Center of Pathology (NCP), Dudelange, Luxembourg
HAAN, Serge ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
MITTELBRONN, Michel ; University of Luxembourg ; Laboratoire National de Santé (LNS), National Center of Pathology (NCP), Dudelange, Luxembourg
MEISER, Johannes ; University of Luxembourg ; Department of Cancer Research (DOCR), Luxembourg Institute of Health, Luxembourg, Luxembourg
POZDEEV, Vitaly ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Vogel, Jörg ; Institute of Molecular Infection Biology, University of Würzburg, Würzburg, Germany ; Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI), Würzburg, D-97080, Germany
Nuciforo, Paolo G; Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain
WILMES, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Systems Ecology
LETELLIER, Elisabeth ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
FNR11282028 - miRMet - Role Of Mir-371-373 Cluster In Tumor Initiation And Metastatic Colonization, 2016 (15/03/2017-14/07/2020) - Elisabeth Letellier FNR10404093 - microCancer - Non-invasive Microbiome-derived Multi-omic Biomarkers For Early-stage Colorectal Cancer Detection, 2015 (01/01/2016-30/04/2019) - Paul Wilmes FNR12554295 - MyoRPROG - Prognostic Gene Classifier In Stage Ii Colorectal Cancer, 2018 (15/09/2018-14/09/2021) - Elisabeth Letellier FNR15718879 - 1cFlex - Understanding The Flexibility Of 1c Metabolism And Its Role During Metastatic Dissemination Of Cancer Cells, 2021 (01/07/2022-30/06/2025) - Johannes Meiser FNR17103240 - CAFinim - Overcoming Resistance: How Cancer-associated Fibroblasts Influence Immunotherapy And Tumor Immunity, 2022 (01/03/2022-28/02/2026) - Cédric Gilson FNR11823097 - MICROH-DTU - Microbiomes In One Health, 2017 (01/09/2018-28/02/2025) - Paul Wilmes FNR10675146 - CANBIO - Training In Cancer Biology: Focus On Tumour Escape Mechanisms, 2015 (15/10/2016-14/04/2023) - Simone Niclou FNR14591557 - MICROH_CRC - Investigating The Role Of The Microbiome In Colorectal Cancer, 2020 (01/06/2021-30/11/2024) - Elisabeth Letellier
Funding text :
We thank the patients who kindly donated their samples and made this study possible. We gratefully acknowledge the contributions of the surgeons and nurses (not listed as co-authors) from the Centre Hospitalier Emile Mayrisch and the H\u00F4pitaux Robert Schuman, as well as the teams from the Laboratoire National de Sant\u00E9 and the Clinical and Epidemiological Investigation Centre of the Luxembourg Institute of Health for their dedicated work with the patients. We also thank Prof. Dr. Michel Mittelbronn and the pathologists and macroscopy team from NCP/LNS. The authors would also like to thank their collaborators at the IBBL, Dr. Fay Betsou, Dr. Nikolai Goncharenko, Dr. Christelle Bahlawane, Am\u00E9lie Gaignaux and Lamia Skhiri for the overall setup of the patient sample collection and the management of the cohort. We would also like to thank the whole team of the Animal Facility at the University of Luxembourg, especially our veterinarian Jennifer Behm and our facility manager Djalil Coowar. We would like to acknowledge the metabolomics platform at Luxembourg Institute of Health and specifically Dr. Nathalie Legrave and Francois Bernardin for their help with sample measurements. Finally, we would like to thank Professor Olivier de Wever for the kind gift of the CT5.3 fibroblasts, Prof. Daniel Slade for the donation of the pan-Fusobacterium membrane antiserum, and Prof. Emma Allen-Vercoe and her lab at the University of Guelph for generously providing the OMP Fn antibody. Parts of the data processing presented in this manuscript were carried out using the HPC facility of the University of Luxembourg (https://hpc.uni.lu). The graphical abstract as well as all experimental schematics were created with BioRender.com (https://biorender.com). This work was supported by the Luxembourg National Research Fund [CORE/C16/BM/11282028 (EL), CORE/C15/BM/10404093 (PW), PoC/18/12554295 (EL), CORE/C21/BM/15718879 (JM), AFR 17103240 (CG), PRIDE Doctoral Research in the scope of the Doctoral Teaching Unit - MICROH PRIDE17/11823097 to MT, and CANBIO PRIDE21/16763386 (CCTB). The study was further supported by the FNR and the Fondation Cancer Luxembourg grant CORE/C20/BM/14591557 (to EL), an FNR matched funding schemes (MFP20/15251414/MelCol PFP, EL), an Internal Research Project at the University of Luxembourg (MiDiCa; EL, PW, SH) as well as an FNRS-T\u00E9l\u00E9vie funding scheme 7.4565.21 and 7.6603.02 to MM, 7.4560.22 to PS and 7.4552.23 to MG, by the Fondation du P\u00E9lican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg (JK, MM, DT, and MT), the Fondation Schumacher (EL), a postdoctoral fellowship from the Swiss National Science Foundation (P500PB_214405, PPE), a postdoctoral fellowship from the Spanish Fundacion Ramon Areces (JAMT), the Fondation Gustave et Simone Pr\u00E9vot (EL). We would like to thank the Fondation Cancer and the University of Luxembourg for their support of the Luxembourgish CRC patient cohort. JV received relevant funding from Deutsche Forschungsgemeinschaft (DFG; SFB 1583/1\u00A0DECIDE, Project number: 492620490, Subproject A09).\u00A0Moreover, this work was supported by Cancer Research UK [grant number C17937/A29070],\u00A0Fondo de Investigaciones Sanitarias (FIS) grant (PI20/00889) from the Instituto de Salud Carlos III (ISCIII) and\u00A0Fundaci\u00F3n Mutua Madrile\u00F1a (MMADRILE\u00D1A/PREMI/2020CCAA_NUCIFORO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.We thank the patients who kindly donated their samples and made this study possible. We gratefully acknowledge the contributions of the surgeons and nurses (not listed as co-authors) from the Centre Hospitalier Emile Mayrisch and the H\u00F4pitaux Robert Schuman, as well as the teams from the Laboratoire National de Sant\u00E9 and the Clinical and Epidemiological Investigation Centre of the Luxembourg Institute of Health for their dedicated work with the patients. We also thank Prof. Dr. Michel Mittelbronn and the pathologists and macroscopy team from NCP/LNS. The authors would also like to thank their collaborators at the IBBL, Dr. Fay Betsou, Dr. Nikolai Goncharenko, Dr. Christelle Bahlawane, Am\u00E9lie Gaignaux and Lamia Skhiri for the overall setup of the patient sample collection and the management of the cohort. We would also like to thank the whole team of the Animal Facility at the University of Luxembourg, especially our veterinarian Jennifer Behm and our facility manager Djalil Coowar. We would like to acknowledge the metabolomics platform at Luxembourg Institute of Health and specifically Dr. Nathalie Legrave and Francois Bernardin for their help with sample measurements. Finally, we would like to thank Professor Olivier de Wever for the kind gift of the CT5.3 fibroblasts, Prof. Daniel Slade for the donation of the pan-Fusobacterium membrane antiserum, and Prof. Emma Allen-Vercoe and her lab at the University of Guelph for generously providing the OMP Fn antibody. Parts of the data processing presented in this manuscript were carried out using the HPC facility of the University of Luxembourg ( https://hpc.uni.lu ). The graphical abstract as well as all experimental schematics were created with BioRender.com ( https://biorender.com ). This work was supported by the Luxembourg National Research Fund [CORE/C16/BM/11282028 (EL), CORE/C15/BM/10404093 (PW), PoC/18/12554295 (EL), CORE/C21/BM/15718879 (JM), AFR 17103240 (CG), PRIDE Doctoral Research in the scope of the Doctoral Teaching Unit - MICROH PRIDE17/11823097 to MT, and CANBIO PRIDE21/16763386 (CCTB). The study was further supported by the FNR and the Fondation Cancer Luxembourg grant CORE/C20/BM/14591557 (to EL), an FNR matched funding schemes (MFP20/15251414/MelCol PFP, EL), an Internal Research Project at the University of Luxembourg (MiDiCa; EL, PW, SH) as well as an FNRS-T\u00E9l\u00E9vie funding scheme 7.4565.21 and 7.6603.02 to MM, 7.4560.22 to PS and 7.4552.23 to MG, by the Fondation du P\u00E9lican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg (JK, MM, DT, and MT), the Fondation Schumacher (EL), a postdoctoral fellowship from the Swiss National Science Foundation (P500PB_214405, PPE), a postdoctoral fellowship from the Spanish Fundacion Ramon Areces (JAMT), the Fondation Gustave et Simone Pr\u00E9vot (EL). We would like to thank the Fondation Cancer and the University of Luxembourg for their support of the Luxembourgish CRC patient cohort. JV received relevant funding from Deutsche Forschungsgemeinschaft (DFG; SFB 1583/1 DECIDE, Project number: 492620490, Subproject A09). Moreover, this work was supported by Cancer Research UK [grant number C17937/A29070], Fondo de Investigaciones Sanitarias (FIS) grant (PI20/00889) from the Instituto de Salud Carlos III (ISCIII) and Fundaci\u00F3n Mutua Madrile\u00F1a (MMADRILE\u00D1A/PREMI/2020CCAA_NUCIFORO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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