Fusobacterium nucleatum (F. nucleatum) is an anaerobic bacterium notably enriched in the gut microbiota of colorectal cancer (CRC) patients and may play a role in CRC both by colonizing tumor cells and suppressing immune mechanisms. Understanding how this bacterium adheres to cancer cells could provide key targets for developing novel antitumor therapies.

Researchers led by Prof. George F. Gao from the Institute of Microbiology of the Chinese Academy of Sciences (CAS) have identified the key mechanism by which F. nucleatum binds to the human cell receptors CEACAM1 and CEACAM5, which are frequently overexpressed on many types of cancer cells.

This work was published in PNAS on September 10.

The adhesion mechanism between pathogenic bacteria and host cells represents a fundamental aspect of pathogenic biology. Such bacteria employ specialized surface molecules called adhesins to establish a tight attachment to host cells via precise molecular interactions. This adhesion process is dynamically regulated during infection, allowing bacteria to adapt to changing conditions. However, how bacteria control the strength of adhesion at the bacterium-host interface was poorly understood until now.

F. nucleatum utilizes its adhesin protein CbpF to specifically bind to CEACAM1 and CEACAM5. Notably, when engaged, CEACAM1 also acts as an inhibitory receptor on immune cells, suppressing immune activity. Therefore, elucidating how CbpF interacts with CEACAM1 and CEACAM5 is critical for designing targeted therapeutic strategies that disrupt bacteria-driven tumor progression.

Using cryo-electron microscopy, the researchers resolved high-resolution structures of CbpF bound to CEACAM1 and CEACAM5. In the complex structures, CbpF assembles as a trimer, with each monomer binding one CEACAM1 or CEACAM5 molecule, forming a symmetric 3:3 binding pattern. 

Additionally, the researchers observed another type of complex, featuring two CbpF trimers bound to a single receptor dimer.

Based on these findings, the researchers proposed a "Velcro model" of bacterial adhesion: The highly flexible CbpF protein acts as the "loop" side, interacting with the host receptor, which serves as the "hook" side, through multiple binding sites. This mechanism allows bacteria to dynamically adjust adhesion strength under mechanical stress, enabling tight attachment and easy detachment when needed for adaptation to complex physiological environments. This model shows how bacteria dynamically regulate adhesion at the molecular level. 

The study was carried out in collaboration with Renji Hospital, the School of Medicine at Shanghai Jiao Tong University, and the Institute of Process Engineering of CAS. It was supported by the National Key Research and Development Program of China.

Structural model of CbpF binding to CEACAM1/CEACAM5 and the proposed "Velcro" adhesion mechanism. (Image by Prof. George F. Gao's group)