Qin Gege, Shao Xiying, Liu Xiaolong, Xu Jiachao, Wang Xiaojia, Wang Wenxi, Gao Lu, Liang Yuxin, Xie Lina, Su Dan, Yang Hongwei, Zhou Wei, Fang Xiaohong
Key Laboratory of Molecular Nanostructure and Nanotechnology, Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310022, Zhejiang, China.
Proc Natl Acad Sci U S A. 2025 Jan 14;122(2):e2421710122. doi: 10.1073/pnas.2421710122. Epub 2025 Jan 9.
Emerging evidence indicates that intratumor bacteria exist as an active and specific tumor component in many tumor types beyond digestive and respiratory tumors. However, the biological impact and responsible molecules of such local bacteria-tumor direct interaction on cancer therapeutic response remain poorly understood. Trastuzumab is among the most commonly used drugs targeting the receptor tyrosine-protein kinase erbB-2 (ErbB2) in breast cancer, but its resistance is inevitable, severely limiting its clinical effectiveness. Here, we demonstrate that the quorum-sensing signaling molecule N-(3-oxo-dodecanoyl) homoserine lactone (3oc), a chemical compound released by (), one tumor-resident bacteria with a relative high abundance in breast cancer, promotes breast cancer cell resistance to trastuzumab. Mechanically, 3oc directly leads to spontaneous dimerization of the transforming growth factor β (TGF-β) type II serine/threonine kinase receptor on the cell membrane in a ligand-independent manner. The 3oc-induced TGF-β signaling subsequently triggers ErbB2 phosphorylation and its downstream target activation, overcoming the inhibition effect of trastuzumab on ErbB2. With specific real-time qPCR, fluorescence in situ hybridization imaging, and liquid chromatography ionization tandem mass spectrometry analyses of clinical samples, we confirmed that and its signaling molecule 3oc exist in breast cancer tissues and there is a clinical correlation between colonization and trastuzumab resistance. This work expands the biological functions of intratumor bacteria in cancer treatment responsiveness and provides a unique perspective for overcoming trastuzumab resistance.
新出现的证据表明，肿瘤内细菌在除消化和呼吸肿瘤之外的多种肿瘤类型中作为一种活跃且特定的肿瘤成分存在。然而，这种局部细菌与肿瘤直接相互作用对癌症治疗反应的生物学影响和相关分子仍知之甚少。曲妥珠单抗是乳腺癌中最常用的靶向受体酪氨酸蛋白激酶erbB-2（ErbB2）的药物之一，但其耐药性不可避免，严重限制了其临床疗效。在此，我们证明群体感应信号分子N-（3-氧代十二烷酰）高丝氨酸内酯（3oc），一种由（）释放的化合物，（）是一种在乳腺癌中相对丰度较高的肿瘤常驻细菌，可促进乳腺癌细胞对曲妥珠单抗的耐药性。从机制上讲，3oc以非配体依赖的方式直接导致细胞膜上转化生长因子β（TGF-β）II型丝氨酸/苏氨酸激酶受体的自发二聚化。3oc诱导的TGF-β信号随后触发ErbB2磷酸化及其下游靶点激活，克服了曲妥珠单抗对ErbB2的抑制作用。通过对临床样本进行特异性实时定量PCR、荧光原位杂交成像和液相色谱电离串联质谱分析，我们证实（）及其信号分子3oc存在于乳腺癌组织中，并且（）的定植与曲妥珠单抗耐药之间存在临床相关性。这项工作扩展了肿瘤内细菌在癌症治疗反应性方面的生物学功能，并为克服曲妥珠单抗耐药性提供了独特的视角。
