Abstract：
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.
摘要：
口腔消化链球菌(P.造口）富含结直肠癌（CRC），但其在CRC中的因果关系和翻译意义尚不清楚。这里,我们表明，在ApcMin/+和氧化偶氮甲烷/葡聚糖硫酸钠（AOM-DSS）模型中，气孔假单胞菌通过诱导细胞增殖加速结肠肿瘤发生，抑制细胞凋亡，并损害肠道屏障功能。口蹄疫杆菌通过其表面蛋白果糖-1,6-二磷酸醛缩酶（FBA）与CRC细胞上的整联蛋白α6/β4受体结合，导致ERBB2和下游MEK-ERK-p90级联的激活。FBA-整合素α6/β4的阻断消除了ERBB2-丝裂原活化蛋白激酶（MAPK）的活化和造口假单胞菌的原瘤作用。造口假单胞菌驱动的ERBB2激活绕过EGFR抑制剂的受体酪氨酸激酶（RTK）阻断（西妥昔单抗，厄洛替尼)，在KRAS野生型CRC的异种移植和自发性CRC模型中导致耐药性。造口假单胞菌还废除了BRAFV600E突变CRC异种移植物中BRAF抑制剂(vemurafenib)的功效。因此，我们确定口臭假单胞菌是一种致癌细菌，也是CRC中对RTK抑制剂无反应的促成因素。
