Peptostreptococcus stomatis promotes colonic tumorigenesis and receptor tyrosine kinase inhibitor resistance by activating ERBB2-MAPK,Cell Host & Microbe

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Peptostreptococcus stomatis promotes colonic tumorigenesis and receptor tyrosine kinase inhibitor resistance by activating ERBB2-MAPK
Cell Host & Microbe ( IF 20.6 ) Pub Date : 2024-07-25 , DOI: 10.1016/j.chom.2024.07.001
Pingmei Huang ₁ , Fenfen Ji ₁ , Alvin Ho-Kwan Cheung ₂ , Kaili Fu ₁ , Qiming Zhou ₁ , Xiao Ding ₁ , Danyu Chen ₁ , Yufeng Lin ₁ , Luyao Wang ₁ , Ying Jiao ₁ , Eagle S H Chu ₁ , Wei Kang ₂ , Ka Fai To ₂ , Jun Yu ₁ , Chi Chun Wong ₁

Affiliation

() is enriched in colorectal cancer (CRC), but its causality and translational implications in CRC are unknown. Here, we show that accelerates colonic tumorigenesis in and azoxymethane/dextran sodium sulfate (AOM-DSS) models by inducing cell proliferation, suppressing apoptosis, and impairing gut barrier function. 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 . -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. also abrogates BRAF inhibitor (vemurafenib) efficacy in BRAF-mutant CRC xenografts. Thus, we identify as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC.

中文翻译：

口腔消化链球菌通过激活 ERBB2-MAPK 促进结肠肿瘤发生和受体酪氨酸激酶抑制剂耐药性

() 在结直肠癌 (CRC) 中丰富，但其在 CRC 中的因果关系和转化意义尚不清楚。在这里，我们发现它通过诱导细胞增殖、抑制细胞凋亡和损害肠道屏障功能来加速氧化偶氮甲烷/葡聚糖硫酸钠（AOM-DSS）模型中的结肠肿瘤发生。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) 的激活和的促肿瘤作用。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。还消除了 BRAF 抑制剂（vemurafenib）在 BRAF 突变 CRC 异种移植物中的功效。因此，我们确定它是一种致癌细菌，也是结直肠癌中对 RTK 抑制剂无反应的促成因素。

更新日期：2024-07-25

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