Abstract 5129: Fusobacterium and co-occurring microbes in primary and metastatic colorectal cancer

Abstract

Abstract In colorectal cancer, malignant cells are surrounded by a complex microenvironment encompassing a range of non-transformed cells, but also a diverse collection of microorganisms. A growing body of evidence demonstrates the role of particular microorganisms in modulating inflammatory environments and promoting tumor growth and metastasis. Studies by our group, and others, reveal a consistent enrichment of Fusobacterium nucleatum in human colorectal cancer, and F. nucleatum has been shown to accelerate tumorigenesis using both in vitro and in vivo preclinical models. We recently demonstrated via microbiome analysis and microbial culture that fusobacteria and its co-occurring microbiota, including Bacteroides, Prevotella and Selenomonas species, persist in liver metastasis of Fusobacterium-positive colorectal cancers. Many of the liver metastasis share the same dominant microbiome (>1% relative abundance) as the paired primary colorectal tumor. Additionally, we have cultured fusobacteria from paired primary and metastatic tumors, and following whole genome sequencing analysis reveal the same strains of Fusobacterium are present in the primary tumors and distant site metastasis, despite the tissue being resected months or even years apart. In situ hybridization analysis demonstrate that Fusobacterium is invasive in the primary tumors and distal metastasis, and is associated with cells whose morphology is consistent with malignant cells. Additionally, we demonstrate via microbiome analysis and microbial culture, that Fusobacterium and its co-occurring microbiome also persist and remain viable in patient derived xenografts of colorectal cancers. Treatment of a patent derived colon cancer xenograft harboring F. nucleatum, with an antibiotic that kills F. nucleatum reduced tumor growth, cancer cell proliferation and tumor fusobacterial load. We have isolated and sequenced the genomes of over 60 F. nucleatum strains from human colorectal cancer tumors with detailed microbiome and patient metadata. In addition to phenotypic analysis and small molecule inhibitory screens of the F. nucleatum colorectal cancer isolates, we are conducting comparative genomic analysis with F. nucleatum isolates from the oral cavity of non-cancer patients to determine colorectal cancer-specific markers and identify targetable genomic attributes. In summary, these findings suggest that the tumor microbiota are intrinsic and essential components of the cancer microenvironment and warrant further investigation into the modulation of the tumor microbiota for the treatment of Fusobacterium-associated colorectal cancer in both early and late stage disease. Citation Format: Susan Bullman, Chandra S. Pedamallu, Ewa Sicinska, Thomas Clancy, Shuji Ogino, Josep Tabernero, Charles Fuchs, William C. Hahn, Paolo Nuciforo, Matthew Meyerson. Fusobacterium and co-occurring microbes in primary and metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5129.