Bacteroides acidifaciens enriched by KRAS mutation promotes colorectal tumorigenesis.

Colorectal cancer (CRC) is a multifactorial disease impacted by the tumor microbiome and host genetics, notably mutations that activate KRAS to stimulate a RAF-MEK-extracellular signal-regulated kinase (ERK) proliferative cascade.

However, whether host genetics interplays with the tumor microbiome remains unclear. Here, we profiled intratumoral microbiomes from KRAS-mutant CRC patients and intestine-specific oncogenic KRASG12D mice, revealing that KRAS reshapes the microbial community, enriching Bacteroides acidifaciens that predicts poor prognosis in KRAS-mutant CRC patients. Employing isogenic CRC cells and mice with or without mutant KRAS, we demonstrate that B. acidifaciens promotes malignant phenotypes in KRAS-mutant CRC cells and intestine-specific KRASG12D mice but not in wild-type counterparts. B. acidifaciens SusF binds and stabilizes ARHGEF2, which promotes active KRAS and RAF-MEK-ERK signaling.

SusF ablation or ARHGEF2 knockout in KRAS-mutant CRC cells abrogates the pro-tumorigenic effects of B. acidifaciens. These observations offer strategies for targeting mutant KRAS-driven B. acidifaciens to mitigate feedforward signaling leading to tumorigenesis.