Wednesday, April 2, 2025
4/2/2025
Deciphering the Critical Determinants of Enteric and Tumor Niche Colonization by Microbes in Colorectal Cancer - PROJECT SUMMARY/ABSTRACT: The proposed study seeks to use the established association of Fusobacterium nucleatum (Fn) with colorectal cancer (CRC) as a model to decipher critical determinants of microbial tumor niche colonization and examine mechanisms by which microbes contribute to CRC. Within the CRC tumor microenvironment (TME), malignant cells are surrounded by a complex range of non-transformed cells and a diverse collection of tumor-infiltrating microorganisms. Fusobacterium nucleatum (Fn), a member of the human oral microbiota, is found enriched in colorectal cancer (CRC) compared to non-cancer colon tissue, across patient cohorts worldwide. Previous work by our group and others has demonstrated that patients with CRC tumors harboring high levels of Fn have poorer survival, that Fn persists in metastatic disease, and that microbiome modulation targeting Fn could change the course of this disease. Additionally, our recent work has demonstrated that Fusobacterium exists within regions of oral and CRC tumors that are poorly vascularized and highly immunosuppressive; characterized by myeloid cell infiltration, upregulation of immune checkpoint proteins PD1, CTLA4 and Lag3, reduced T-cell infiltration - the same regions that are recalcitrant to immunotherapies and chemotherapeutics, thus supportive of cancer progression. However, mechanistic insights into how this microbe is homing to and colonizing the TME and how it is contributing to disease initiation or progression are severely lacking, which impedes prophylactic and therapeutic progress against Fn in cancer. Here, in preliminary studies, we isolated and characterized the genomes and epigenomes of >150 Fn strains from CRC tumors and the oral cavity and discovered that within Fn subspecies animalis, there are two distinct clades that differ in their enrichment in CRC, which we named Fna oral-clade and Fna CRC-clade. We show that Fna CRC-clade is the only Fn group significantly enriched in human tumors and fecal specimens. Pangenomic investigations of Fna clades revealed genetic factors whose putative functions are canonically associated with pathogenic colonization of the human gastrointestinal (GI) tract. These included operons for the metabolic utilization of the gastric substrates ethanolamine (EA) and 1,2-propanediol (1,2-PD), and a glutamate decarboxylase acid resistance (AR2) system (associated with extreme acid resistance) of relevance to survival during GI transit and immune-modulation in the TME. This proposal’s objective is to interrogate these genetic factors, enriched in Fna CRC-clade but absent in oral-clade, as critical determinants of gastrointestinal transit, colonization, and survival within CRC tumors. Our team brings together expertise in synthetic microbiology, pangenomics, and genetic engineering (PI Johnston), preclinical cancer models, and tumor-infiltrating microbiota (PI Bullman), in addition to metabolomics (Co-I Raftery). Thus, we are poised to provide mechanistic insights on the genetic basis of Fna’s pathoadaptation to CRC and could identify new therapeutic targets against this tumor-infiltrating microbe found enriched in CRC-patient cohorts worldwide.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).