A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche

Martha Zepeda-Rivera, Samuel S. Minot, Heather Bouzek, Hanrui Wu, Aitor Blanco-Míguez, Paolo Manghi, Dakota S. Jones, Kaitlyn D. LaCourse, Ying Wu, Elsa F. McMahon, Soon-Nang Park, Yun K. Lim, Andrew G. Kempchinsky, Amy D. Willis, Sean L. Cotton, Susan C. Yost, Ewa Sicinska, Joong-Ki Kook, Floyd E. Dewhirst, Nicola Segata, Susan Bullman () and Christopher D. Johnston ()
Additional contact information
Martha Zepeda-Rivera: Fred Hutchinson Cancer Center
Samuel S. Minot: Fred Hutchinson Cancer Center
Heather Bouzek: Fred Hutchinson Cancer Center
Hanrui Wu: Fred Hutchinson Cancer Center
Aitor Blanco-Míguez: University of Trento
Paolo Manghi: University of Trento
Dakota S. Jones: Fred Hutchinson Cancer Center
Kaitlyn D. LaCourse: Fred Hutchinson Cancer Center
Ying Wu: Fred Hutchinson Cancer Center
Elsa F. McMahon: Fred Hutchinson Cancer Center
Soon-Nang Park: Chosun University
Yun K. Lim: Chosun University
Andrew G. Kempchinsky: Fred Hutchinson Cancer Center
Amy D. Willis: University of Washington
Sean L. Cotton: Forsyth Institute
Susan C. Yost: Forsyth Institute
Ewa Sicinska: Dana-Farber Cancer Institute
Joong-Ki Kook: Chosun University
Floyd E. Dewhirst: Forsyth Institute
Nicola Segata: University of Trento
Susan Bullman: Fred Hutchinson Cancer Center
Christopher D. Johnston: Fred Hutchinson Cancer Center

Nature, 2024, vol. 628, issue 8007, 424-432

Abstract: Abstract Fusobacterium nucleatum (Fn), a bacterium present in the human oral cavity and rarely found in the lower gastrointestinal tract of healthy individuals1, is enriched in human colorectal cancer (CRC) tumours2–5. High intratumoural Fn loads are associated with recurrence, metastases and poorer patient prognosis5–8. Here, to delineate Fn genetic factors facilitating tumour colonization, we generated closed genomes for 135 Fn strains; 80 oral strains from individuals without cancer and 55 unique cancer strains cultured from tumours from 51 patients with CRC. Pangenomic analyses identified 483 CRC-enriched genetic factors. Tumour-isolated strains predominantly belong to Fn subspecies animalis (Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (Fna C1 and Fna C2). Of these, only Fna C2 dominates the CRC tumour niche. Inter-Fna analyses identified 195 Fna C2-associated genetic factors consistent with increased metabolic potential and colonization of the gastrointestinal tract. In support of this, Fna C2-treated mice had an increased number of intestinal adenomas and altered metabolites. Microbiome analysis of human tumour tissue from 116 patients with CRC demonstrated Fna C2 enrichment. Comparison of 62 paired specimens showed that only Fna C2 is tumour enriched compared to normal adjacent tissue. This was further supported by metagenomic analysis of stool samples from 627 patients with CRC and 619 healthy individuals. Collectively, our results identify the Fna clade bifurcation, show that specifically Fna C2 drives the reported Fn enrichment in human CRC and reveal the genetic underpinnings of pathoadaptation of Fna C2 to the CRC niche.

Date: 2024
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DOI: 10.1038/s41586-024-07182-w

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