# Fusobacterium nucleatum Lipopolysaccharides Disrupt the Interaction of Siglec‑7 to Sialoglycans Expressed on Mammalian Cells

## TL;DR

This study shows how LPS from Fusobacterium nucleatum disrupts Siglec-7 binding to sialic acids, offering new insights for colon cancer treatments.

## Contribution

Fn LPS is identified as a novel ligand for Siglec-7, with carbohydrate-mediated disruption of immune interactions.

## Key findings

- Fn LPS binds to Siglec-7 through the carbohydrate-binding V-set domain.
- Fn LPS disrupts Siglec-7 binding to sialic acids on mammalian cells in a carbohydrate-dependent manner.
- These findings suggest glycomimetic strategies could help limit colon cancer progression.

## Abstract

Sialic acid-binding immunoglobulin-like lectins (Siglecs)
are key
immune receptors that bind to cell surface sialic acids, leading to
modulation of the immune system. Interrupting the Siglec–sialoglycan
binding in cancer has been proposed as a potential antitumor response
strategy. We previously showed that colon-cancer-associated Fusobacterium nucleatum (Fn) ATCC 51191 interacts
with Siglec-7 via its lipopolysaccharide (LPS), revealing Fn LPS as
a new ligand for Siglec-7. Here, we used glycoengineered cells carrying
sialic acid variants to investigate the capacity of LPS isolated from F. nucleatum strains to disrupt the interaction between
sialic acid expressed on mammalian cells and Siglec-7. We first showed
that LPS extracted from Fusobacterium polymorphum ATCC 10953, F. nucleatum ssp. animalis ATCC 51191, and F. nucleatum ssp. nucleatum ATCC 25586 strains
bound to recombinant Siglec-7 in vitro, while no binding was observed
with the Siglec-7R124A mutant, suggesting that the binding occurred
through the carbohydrate binding V-set domain. Using glycoengineered
Jurkat cells and HEK293T cells carrying modified sialic acid forms,
we demonstrated that F. nucleatum LPS
could significantly disrupt the binding of Siglec-7 to these cells
and that this inhibition was decreased following neuraminidase treatment,
confirming that the interaction between Fn LPS and Siglec-7 is carbohydrate-mediated.
We further validated these data using Jurkat cells and HEK293T cells
expressing high-affinity sialic acid ligands. We showed that F. nucleatum LPS significantly disrupted the binding
of Siglec-7 to these cells in a specific manner. These findings offer
novel insights into the development of glycomimetic approaches for
limiting colon cancer progression.