口腔消化链球菌 (P.ostomatis) 在结直肠癌 (CRC) 中富集，但其在 CRC 中的因果关系和转化意义尚不清楚。在这里，我们发现，口腔假单胞菌通过诱导细胞增殖、抑制细胞凋亡和损害肠道屏障功能，在 ApcMin/ 和氧化偶氮甲烷/葡聚糖硫酸钠 (AOM-DSS) 模型中加速结肠肿瘤发生。 P. stomatis 通过其表面蛋白果糖-1,6-二磷酸醛缩酶 (FBA) 粘附在 CRC 细胞上，FBA 与 CRC 细胞上的整合素 α6/β4 受体结合，导致 ERBB2 和下游 MEK-ERK-p90 级联的激活。阻断 FBA 整合素 α6/β4 可消除 ERBB2 丝裂原激活蛋白激酶 (MAPK) 激活和口腔假单胞菌的促肿瘤作用。口腔假单胞菌驱动的 ERBB2 激活绕过了 EGFR 抑制剂（西妥昔单抗、厄洛替尼）对受体酪氨酸激酶 (RTK) 的阻断，导致 KRAS 野生型 CRC 的异种移植和自发 CRC 模型中产生耐药性。 P. stomatis 还会消除 BRAF 抑制剂（vemurafenib）在 BRAFV600E 突变 CRC 异种移植物中的功效。因此，我们将口腔假单胞菌确定为一种致癌细菌，也是 CRC 中对 RTK 抑制剂无反应的影响因素。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.