The gut microbial metabolite formate exacerbates colorectal cancer progression

Abstract

The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium nucleatum, promotes CRC development. We describe molecular signatures linking CRC phenotypes with Fusobacterium abundance. Cocultures of F. nucleatum with patient-derived CRC cells display protumorigenic effects, along with a metabolic shift towards increased formate secretion and cancer glutamine metabolism. We further show that microbiome-derived formate drives CRC tumour invasion by triggering AhR signalling, while increasing cancer stemness. Finally, F. nucleatum or formate treatment in mice leads to increased tumour incidence or size, and Th17 cell expansion, which can favour proinflammatory profiles. Moving beyond observational studies, we identify formate as a gut-derived oncometabolite that is relevant for CRC progression.

Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells

“…Fn reportedly activates Wnt signaling [ 8 ] and produces CSC characteristics and a mesenchymal phenotype in CRC cells [ 17 , 18 ]. The results depicted in Figure 3 complement this information, showing that, although constitutively active, the Wnt cascade can be further stimulated by Fn in CSC, as revealed by the increased inhibitory phosphorylation of the β-catenin destruction factor GSK3β [ 31 ] and by the induction of TCF/LEF-driven recombinant GFP.…”

“…It is, however, known that colorectal-tumor-initiating cells exploit autocrine cytokine-triggered circuitries to resist chemotherapy-induced cell death [ 15 ], and that normal intestinal stem cells express innate immune receptors that mediate protection from oxidative damage and ROS cytotoxicity in response to bacterial components [ 16 ]. Additionally, Fn induces CSC-like traits in cultured CRC lines via epithelial–mesenchymal transition (EMT) [ 17 ], and the Fn -derived metabolite formate enhances the stemness and self-renewal capacity of patient-derived colorectal tumor organoids [ 18 ].…”

How a Formate Dehydrogenase Responds to Oxygen: Unexpected O2 Insensitivity of an Enzyme Harboring Tungstopterin, Selenocysteine, and [4Fe–4S] Clusters

“…The simplest carboxylic acid (formic acid) and its conjugate base (formate) are normal products of metabolic activity in living organisms, including bacteria and humans . However, formate derived from human gut microbiota metabolism drives inflammatory dysbiosis and progression of colorectal cancer . Although formic acid is primarily used as a food preservative (E236) or as a silage additive for maintaining the nutritive value of animal feed, it is a highly sought-after electron-mediator and feedstock in (electro)­microbial bioproduction, as well as a low carbon-footprint molecule that serves as a chemically robust hydrogen storage medium. , In addition to being a carbon and energy source for the anaerobic and aerobic growth of disparate bacteria, archaea, , and syntrophic consortia, formate can be generated abiotically from CO 2 and renewable electricity …”

Fusobacterium nucleatum and Malignant Tumors of the Digestive Tract: A Mechanistic Overview

“…The results of a metagenomic analysis found that F. nucleatum proved to be an important marker of colorectal carcinogenesis and tumor aggressiveness [ 27 ]. A co-culture of F. nucleatum and CRC cells could increase formate secretion and cancer glutamine metabolism, which drove CRC tumor invasion and proliferation by triggering aryl hydrocarbon receptor (AhR) signaling [ 28 ]. F. nucleatum was associated with the elevation of angiopoietin-like 4 protein (ANGPTL4) expression in CRC cells, thus increasing glycolytic activity, which plays an important role in F. nucleatum colonization and proliferation in CRC [ 29 ].…”