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, José Alberto Molina‐Tijeras, Catarina Correia Tavares Bernardino, Falk Ponath, Anaïs 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 Nucíforo, Paul Wilmes, Elisabeth Letellier
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.