Fusobacterium nucleatum interacts with cancer-associated fibroblasts to promote colorectal cancer

Jessica Karta; Marianne Meyers; Fabien Rodriguez; Eric Koncina; Cedric Gilson; Eliane Klein; Monica Gabola; Mohaned Benzarti; Pau Pérez Escriva; Jose Alberto Molina Tijeras; Catarina Correia Tavares Bernardino; Falk Ponath; Anais Carpentier; Mònica Aguilera Pujabet; Maryse Schmoetten; Mina Tsenkova; Perla Saoud; Anthoula Gaigneaux; Dominik Ternes; Lidia Alonso; Nikolaus Zügel; Eric Willemssen; Philippe Koppes; Daniel Léonard; Luis Perez Casanova; Serge Haan; Michel Mittelbronn; Johannes Meiser; Vitaly I. Pozdeev; Jörg Vogel; Paolo G. Nuciforo; Paul Wilmes; Elisabeth Letellier

doi:10.1038/s44318-025-00542-w

Fusobacterium nucleatum interacts with cancer-associated fibroblasts to promote colorectal cancer

Jessica Karta, Marianne Meyers, Fabien Rodriguez, Eric Koncina, Cedric Gilson, Eliane Klein, Monica Gabola, Mohaned Benzarti, Pau Pérez Escriva, Jose Alberto Molina Tijeras, Catarina Correia Tavares Bernardino, Falk Ponath, Anais Carpentier, Mònica Aguilera Pujabet, Maryse Schmoetten, Mina Tsenkova, Perla Saoud, Anthoula Gaigneaux, Dominik Ternes, Lidia AlonsoNikolaus Zügel, Eric Willemssen, Philippe Koppes, Daniel Léonard, Luis Perez Casanova, Serge Haan, Michel Mittelbronn, Johannes Meiser, Vitaly I. Pozdeev, Jörg Vogel, Paolo G. Nuciforo, Paul Wilmes, Elisabeth Letellier^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

1 Citation (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	5375-5393
Number of pages	19
Journal	EMBO Journal
Volume	44
Issue number	19
Early online date	22 Aug 2025
DOIs	https://doi.org/10.1038/s44318-025-00542-w
Publication status	Published - Oct 2025

Keywords

Cancer-associated Fibroblasts (CAFs)
Colorectal Cancer
Fusobacterium nucleatum
Inflammatory CAF (iCAF)
Invasion
Reactive Oxygen Species/metabolism
Fusobacterium nucleatum/physiology
Humans
Coculture Techniques
Gastrointestinal Microbiome
Tumor Microenvironment
Cancer-Associated Fibroblasts/microbiology
Animals
Fusobacterium Infections/microbiology
Cell Line, Tumor
Colorectal Neoplasms/microbiology
Mice
Cytokines/metabolism

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Karta, J., Meyers, M., Rodriguez, F., Koncina, E., Gilson, C., Klein, E., Gabola, M., Benzarti, M., Pérez Escriva, P., Molina Tijeras, J. A., Correia Tavares Bernardino, C., Ponath, F., Carpentier, A., Pujabet, M. A., Schmoetten, M., Tsenkova, M., Saoud, P., Gaigneaux, A., Ternes, D., ... Letellier, E. (2025). Fusobacterium nucleatum interacts with cancer-associated fibroblasts to promote colorectal cancer. EMBO Journal, 44(19), 5375-5393. https://doi.org/10.1038/s44318-025-00542-w

@article{0324d3f8e3aa4b69b3e5b2548f21eb97,

title = "Fusobacterium nucleatum interacts with cancer-associated fibroblasts to promote colorectal cancer",

abstract = "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.",

keywords = "Cancer-associated Fibroblasts (CAFs), Colorectal Cancer, Fusobacterium nucleatum, Inflammatory CAF (iCAF), Invasion, Reactive Oxygen Species/metabolism, Fusobacterium nucleatum/physiology, Humans, Coculture Techniques, Gastrointestinal Microbiome, Tumor Microenvironment, Cancer-Associated Fibroblasts/microbiology, Animals, Fusobacterium Infections/microbiology, Cell Line, Tumor, Colorectal Neoplasms/microbiology, Mice, Cytokines/metabolism",

author = "Jessica Karta and Marianne Meyers and Fabien Rodriguez and Eric Koncina and Cedric Gilson and Eliane Klein and Monica Gabola and Mohaned Benzarti and \{P{\'e}rez Escriva\}, Pau and \{Molina Tijeras\}, \{Jose Alberto\} and \{Correia Tavares Bernardino\}, Catarina and Falk Ponath and Anais Carpentier and Pujabet, \{M{\`o}nica Aguilera\} and Maryse Schmoetten and Mina Tsenkova and Perla Saoud and Anthoula Gaigneaux and Dominik Ternes and Lidia Alonso and Nikolaus Z{\"u}gel and Eric Willemssen and Philippe Koppes and Daniel L{\'e}onard and Casanova, \{Luis Perez\} and Serge Haan and Michel Mittelbronn and Johannes Meiser and Pozdeev, \{Vitaly I.\} and J{\"o}rg Vogel and Nuciforo, \{Paolo G.\} and Paul Wilmes and Elisabeth Letellier",

note = "Funding: 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{\'e}l{\'e}vie 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{\'e}lican 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{\'e}vot (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{\'o}n Mutua Madrile{\~n}a (MMADRILE{\~N}A/PREMI/ 2020CCAA\_NUCIFORO). Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = oct,

doi = "10.1038/s44318-025-00542-w",

language = "English",

volume = "44",

pages = "5375--5393",

journal = "EMBO Journal",

issn = "0261-4189",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "19",

}

Karta, J, Meyers, M, Rodriguez, F, Koncina, E, Gilson, C, Klein, E, Gabola, M, Benzarti, M, Pérez Escriva, P, Molina Tijeras, JA, Correia Tavares Bernardino, C, Ponath, F, Carpentier, A, Pujabet, MA, Schmoetten, M, Tsenkova, M, Saoud, P, Gaigneaux, A, Ternes, D, Alonso, L, Zügel, N, Willemssen, E, Koppes, P, Léonard, D, Casanova, LP, Haan, S, Mittelbronn, M, Meiser, J, Pozdeev, VI, Vogel, J, Nuciforo, PG, Wilmes, P & Letellier, E 2025, 'Fusobacterium nucleatum interacts with cancer-associated fibroblasts to promote colorectal cancer', EMBO Journal, vol. 44, no. 19, pp. 5375-5393. https://doi.org/10.1038/s44318-025-00542-w

TY - JOUR

T1 - Fusobacterium nucleatum interacts with cancer-associated fibroblasts to promote colorectal cancer

AU - Karta, Jessica

AU - Meyers, Marianne

AU - Rodriguez, Fabien

AU - Koncina, Eric

AU - Gilson, Cedric

AU - Klein, Eliane

AU - Gabola, Monica

AU - Benzarti, Mohaned

AU - Pérez Escriva, Pau

AU - Molina Tijeras, Jose Alberto

AU - Correia Tavares Bernardino, Catarina

AU - Ponath, Falk

AU - Carpentier, Anais

AU - Pujabet, Mònica Aguilera

AU - Schmoetten, Maryse

AU - Tsenkova, Mina

AU - Saoud, Perla

AU - Gaigneaux, Anthoula

AU - Ternes, Dominik

AU - Alonso, Lidia

AU - Zügel, Nikolaus

AU - Willemssen, Eric

AU - Koppes, Philippe

AU - Léonard, Daniel

AU - Casanova, Luis Perez

AU - Haan, Serge

AU - Mittelbronn, Michel

AU - Meiser, Johannes

AU - Pozdeev, Vitaly I.

AU - Vogel, Jörg

AU - Nuciforo, Paolo G.

AU - Wilmes, Paul

AU - Letellier, Elisabeth

N1 - Funding: 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-Télévie 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 Pélican 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 Prévot (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 Fundación Mutua Madrileña (MMADRILEÑA/PREMI/ 2020CCAA_NUCIFORO). Publisher Copyright: © The Author(s) 2025.

PY - 2025/10

Y1 - 2025/10

N2 - 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.

AB - 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.

KW - Cancer-associated Fibroblasts (CAFs)

KW - Colorectal Cancer

KW - Fusobacterium nucleatum

KW - Inflammatory CAF (iCAF)

KW - Invasion

KW - Reactive Oxygen Species/metabolism

KW - Fusobacterium nucleatum/physiology

KW - Humans

KW - Coculture Techniques

KW - Gastrointestinal Microbiome

KW - Tumor Microenvironment

KW - Cancer-Associated Fibroblasts/microbiology

KW - Animals

KW - Fusobacterium Infections/microbiology

KW - Cell Line, Tumor

KW - Colorectal Neoplasms/microbiology

KW - Mice

KW - Cytokines/metabolism

UR - https://www.scopus.com/pages/publications/105013750720

UR - https://pubmed.ncbi.nlm.nih.gov/40846900/

U2 - 10.1038/s44318-025-00542-w

DO - 10.1038/s44318-025-00542-w

M3 - Article

C2 - 40846900

AN - SCOPUS:105013750720

SN - 0261-4189

VL - 44

SP - 5375

EP - 5393

JO - EMBO Journal

JF - EMBO Journal

IS - 19

ER -

Fusobacterium nucleatum interacts with cancer-associated fibroblasts to promote colorectal cancer

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