Peptostreptococcus stomatis promotes colonic tumorigenesis and receptor tyrosine kinase inhibitor resistance by activating ERBB2-MAPK.
Pingmei HuangFenfen JiAlvin Ho-Kwan CheungKaili FuQiming ZhouXiao DingDanyu ChenYufeng LinLuyao WangYing JiaoEagle S H ChuWei KangKa Fai ToJun YuChi Chun WongPublished in: Cell host & microbe (2024)
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.
Keyphrases
- tyrosine kinase
- wild type
- epidermal growth factor receptor
- signaling pathway
- cell cycle arrest
- pi k akt
- induced apoptosis
- cell proliferation
- oxidative stress
- cell death
- emergency department
- small cell lung cancer
- metastatic colorectal cancer
- radiation therapy
- binding protein
- squamous cell carcinoma
- small molecule
- cell migration
- transcription factor
- amino acid
- adverse drug