Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc

Abstract

SUMMARY Fusobacterium nucleatum is associated with colorectal cancer and promotes colonic tumor formation in preclinical models. However, fusobacteria are core members of the human oral microbiome and less prevalent in the healthy gut, raising questions about how fusobacteria localize to CRC. We identify a host polysaccharide and fusobacterial lectin that explicates fusobacteria abundance in CRC. Gal-Gal-NAc, which is overexpressed in CRC, is recognized by fusobacterial Fap2, which functions as a Gal-Gal-NAc lectin. F. nucleatum binding to clinical adenocarcinomas correlates with Gal-GalNAc expression and is reduced upon O-glycanase treatment. Clinical fusobacteria strains naturally lacking Fap2 or inactivated Fap2 mutants show reduced binding to Gal-GalNAc-expressing CRC cells and established CRCs in mice. Additionally, intravenously injected F. nucleatum localizes to mouse tumor tissues in a Fap2-dependent manner, suggesting that fusobacteria use a hematogenous route to reach colon adenocarcinomas. Thus, targeting F. nucleatum Fap2 or host epithelial Gal-GalNAc may reduce fusobacteria potentiation of CRC.

Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy

“…F. nucleatum attaches to the host epithelial E-cadherin and promotes colorectal carcinogenesis via the fusobacterial adhesin FadA(Rubinstein et al, 2013). The interaction between a host polysaccharide, Gal-GalNAc with fusobacterial lectin (Fap2) facilitates F. nucleatum enrichment in CRC tissues (Abed et al, 2016). However, it is unknown whether and how F. nucleatum may mediate chemoresistance in CRC.…”

“…F. nucleatum adhesin FadA may bind to the E-cadherin protein and promote colorectal carcinogenesis (Rubinstein et al, 2013). In addition, F. nucleatum lectin Fap2 may recognize the host Gal-GalNAc and help this bacterium localize abundantly in colon cancer epithelial cells (Abed et al, 2016). However, the potential effect of F. nucleatum on chemotherapy is not examined in human literature.…”

Synthesis of multi-omic data and community metabolic models reveals insights into the role of hydrogen sulfide in colon cancer

“…On one hand, hydrogen sulfide produced by F. nucleatum or other microbial species may be promoting tumorigenesis by damaging host cells and DNA. Indeed, F. nucelatum has well established mechanistic links to CRC tumor development [37,63–65], albeit, unrelated to hydrogen sulfide production. On the other hand, metabolomics profiles identify no source agent (host, microbe, microbial species).…”

“…In contrast, quantifying the relative abundance of hydrogen sulfide-producing bacteria is far less challenging. Sulfidogenic bacteria such as Bilophila wadsworthia , Fusobacterium species, and sulfur-reducers such as Desulfovibrio species have all been identified within the gut and linked to colon inflammation [32], adenomas [21,33,34], and colon tumors [35–37]. However, these microbial associations are not sufficient for determining microbial metabolite production.…”

<i>Fusobacterium nucleatum</i> Infection in Colorectal Cancer: Linking Inflammation, DNA Mismatch Repair and Genetic and Epigenetic Alterations

“…When its ligands (for instance, Fap2) bind to TIGIT, NK cells stop killing their target cancer cells. Coppenhagen-Glazer et al demonstrated that Fap2 co-aggregates other microorganisms and attaches to the mammalian cell surface by binding to galactose- and N-acetyl-d-galactosamine (Gal / GalNAc) (78). Abed et al showed evidence that enrichment of Fn in CRC tumor tissues, as opposed to normal tissues surrounding these tissues, may be due to selective binding of Fap2 to Gal/GalNAc, which is over expressed on the surface of tumor cells (78).…”