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

作者：Pingmei Huang, Fenfen Ji, Alvin H.K. Cheung, Kaili Fu, Qiming Zhou, Xiao Qiang Ding, Danyu Chen, Yufeng Lin, Luyao Wang, Ying Jiao, Eagle SH Chu, Wei Kang, Ka‐Fai To, Jun Yu, Chi Chun Wong · 发表于：Cell Host & Microbe · 年份：2024 · DOI：10.1016/j.chom.2024.07.001 · 被引用次数：73 · 研究领域：Microbial Metabolism and Applications、Berberine and alkaloids research、Microbial Natural Products and Biosynthesis

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 Apc Min/+ 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 BRAF V600E -mutant CRC xenografts. Thus, we identify P. stomatis as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC.