Deciphering the role of colorectal cancer-associated bacteria in the fibroblast-tumor cell interaction

Dysbiosis is an imbalance in the gut microbiome that is often associated with inflammation and cancer. Several microbial species, such as Fusobacterium nucleatum, have been suggested to be involved in colorectal cancer (CRC). To date, most studies have focused on the interaction between CRC-associated bacteria and tumor cells. However, the tumor microenvironment (TME) is composed of various types of cells, among which cancer-associated fibroblasts (CAFs), one of the most vital players in the TME. The interaction between CRC-associated bacteria and CAFs and especially the impact of their cross-talk on tumor cells, remains largely unknown. In this regard, this thesis investigated the interaction between a well described and accepted CRC-associated bacteria, Fusobacterium nucleatum, and CAFs and their subsequent effects on tumor progression in CRC. Our findings show that F.nucleatum binds to CAFs and induces phenotypic changes. F.nucleatum promotes CAFs to secrete several pro-inflammatory cytokines and membrane-associated proteases. Upon exposure with F.nucleatum, CAFs also undergo metabolic rewiring with higher mitochondrial ROS and lactate secretion. Importantly, F.nucleatum-treated CAFs increase the migration ability of tumor cells in vitro through secreted cytokines, among which CXCL1. Furthermore, the co-injection of F.nucleatum-treated CAFs with tumor cells in vivo leads to a faster tumor growth as compared to the co-injection of untreated CAFs with tumor cells. Taken together, our results show that CAFs are an important player in the gut microbiome-CRC axis. Targeting the CAF-microbiome crosstalk might represent a novel therapeutic strategy for CRC.