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 -