Genetic variants of the transporter SLC22A4 affect the abundance and survival of Fusobacterium nucleatum in colorectal cancer

: The intestinal microbiota influences colorectal cancer (CRC) development, but its interactions with the host's genetic profile during tumorigenesis are poorly understood. We quantified the CRC-associated pathobiont Fusobacterium nucleatum (F. nucleatum) and the commensal Escherichia coli (E. coli) in 99 cases of archival colorectal cancer and adjacent normal mucosa. Tissues were genotyped for the 503F variant of the Organic Cation Transporter OCTN1/SLC22A4. Colorectal cancer stem cells engineered to express the variant were infected with F. nucleatum in vitro. F. nucleatum was similarly present in colorectal cancer tissues and the adjacent normal mucosa, but the F. nucleatum/E. coli ratio was significantly higher in tumors (303.82 vs 30.86, p-value = 0.0396), in a fashion that steadily increased with the number of mutant SLC22A4 alleles (23.48, 159.56, and 211.03 for 0, 1, or 2 T alleles; p = 0.0215). Colon cancer spheroids overexpressing the 503F variant, but not the wild-type allele, displayed attenuated inflammatory response to F. nucleatum and impaired bacterial clearance, mechanistically linking SLC22A4 function and intratumoral F. nucleatum abundance. Thus, genetic variants of the intestinal carrier SLC22A4 shape the intratumor microbiota in favor of a pro-carcinogenic pathobiont by dampening innate immunity and increasing the tolerance of cancerous cells to bacterial invasion.