Peptostreptococcus stomatis promotes colonic tumorigenesis and receptor tyrosine kinase inhibitor resistance by activating ERBB2-MAPK

Peptostreptococcus stomatis (P. stomatis) is enriched in colorectal cancer (CRC), but its causality and translational implications in CRC are unknown. Here, we show that P. stomatis accelerates colonic tumorigenesis in ApcMin/+ and azoxymethane/dextran sodium sulfate (AOM-DSS) models by inducing cell proliferation, suppressing apoptosis, and impairing gut barrier function. P. stomatis adheres to CRC cells through its surface protein fructose-1,6-bisphosphate aldolase (FBA) that binds to the integrin α6/β4 receptor on CRC cells, leading to the activation of ERBB2 and the downstream MEK-ERK-p90 cascade. Blockade of the FBA-integrin α6/β4 abolishes ERBB2-mitogen-activated protein kinase (MAPK) activation and the protumorigenic effect of P. stomatis. P. stomatis-driven ERBB2 activation bypasses receptor tyrosine kinase (RTK) blockade by EGFR inhibitors (cetuximab, erlotinib), leading to drug resistance in xenograft and spontaneous CRC models of KRAS-wild-type CRC. P. stomatis also abrogates BRAF inhibitor (vemurafenib) efficacy in BRAFV600E-mutant CRC xenografts. Thus, we identify P. stomatis as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC. [Display omitted] •P. stomatis is enriched in CRC patients and promotes colorectal tumorigenesis in mice•P. stomatis attaches to CRC cells via binding of its adhesin FBA to integrin α6/β4•P. stomatis induces ERBB2-MEK-ERK-p90 cascade to promote tumorigenesis•P. stomatis-driven ERBB2 activation abrogates RTK inhibitor efficacy in CRC Huang et al. identify a CRC-enriched bacterium, Peptostreptococcus stomatis, that promotes colorectal tumorigenesis. P. stomatis directly interacts with CRC cells via binding of its adhesin FBA to the host integrin α6/β4, leading to ERBB2-MAPK activation. P. stomatis-mediated ERBB2-MAPK signaling contributes to resistance to multiple receptor tyrosine kinase inhibitors in CRC.