口腔普氏链球菌通过激活ERBB2-MAPK促进结肠肿瘤发生和受体酪氨酸激酶抑制剂的抗药性

IF 20.6 1区 医学 Q1 MICROBIOLOGY
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引用次数: 0

摘要

口腔普氏链球菌(P. stomatis)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 P. stomatis 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)粘附于CRC细胞,FBA与CRC细胞上的整合素α6/β4受体结合,导致ERBB2和下游的MEK-ERK-p90级联活化。阻断FBA-整合素α6/β4可消除ERBB2-中性粒细胞活化蛋白激酶(MAPK)的活化和P. stomatis的促瘤效应。P.stomatis驱动的ERBB2活化可绕过表皮生长因子受体抑制剂(西妥昔单抗、厄洛替尼)对受体酪氨酸激酶(RTK)的阻断,从而导致KRAS-wild型CRC异种移植和自发CRC模型产生耐药性。在 BRAFV600E 突变的 CRC 异种移植物中,P. stomatis 也会削弱 BRAF 抑制剂(vemurafenib)的疗效。因此,我们发现口疮桿菌是一种致癌细菌,也是导致 CRC 对 RTK 抑制剂无效的一个因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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.

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来源期刊
Cell host & microbe
Cell host & microbe 生物-微生物学
CiteScore
45.10
自引率
1.70%
发文量
201
审稿时长
4-8 weeks
期刊介绍: Cell Host & Microbe is a scientific journal that was launched in March 2007. The journal aims to provide a platform for scientists to exchange ideas and concepts related to the study of microbes and their interaction with host organisms at a molecular, cellular, and immune level. It publishes novel findings on a wide range of microorganisms including bacteria, fungi, parasites, and viruses. The journal focuses on the interface between the microbe and its host, whether the host is a vertebrate, invertebrate, or plant, and whether the microbe is pathogenic, non-pathogenic, or commensal. The integrated study of microbes and their interactions with each other, their host, and the cellular environment they inhabit is a unifying theme of the journal. The published work in Cell Host & Microbe is expected to be of exceptional significance within its field and also of interest to researchers in other areas. In addition to primary research articles, the journal features expert analysis, commentary, and reviews on current topics of interest in the field.
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