使用艰难梭菌毒素 B 片段靶向抑制 Wnt 信号传导可抑制乳腺癌肿瘤的生长。
Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth.
发表日期：2023 Nov
作者：
Aina He, Songhai Tian, Oded Kopper, Daniel J Horan, Peng Chen, Roderick T Bronson, Ren Sheng, Hao Wu, Lufei Sui, Kun Zhou, Liang Tao, Quan Wu, Yujing Huang, Zan Shen, Sen Han, Xueqing Chen, Hong Chen, Xi He, Alexander G Robling, Rongsheng Jin, Hans Clevers, Dongxi Xiang, Zhe Li, Min Dong
来源：
GENES & DEVELOPMENT
摘要：
Wnt 信号通路通过人类 10 个同源卷曲受体 (FZD1-10) 传递。广泛抑制 Wnt 信号通路的试剂可以减少许多肿瘤的生长和转移，但其治疗方法的开发却因副作用而受到阻碍。针对癌细胞中富集的特定 Wnt-FZD 对的抑制剂可能会减少副作用，但窄谱 Wnt-FZD 抑制剂的体内治疗效果仍有待确定。在这里，我们开发了艰难梭菌毒素 B (TcdBFBD) 的片段，它识别并抑制 FZD 的一个亚类 FZD1/2/7，并检查了靶向该 FZD 亚类是否可以为治疗小鼠乳腺癌模型提供治疗益处。利用 2 个基底样乳腺癌模型和 1 个管腔样乳腺癌模型，我们发现 TcdBFBD 可以减少肿瘤起始细胞并减弱基底样乳腺肿瘤类器官和异种移植肿瘤的生长，而不会损害体内 Wnt 敏感组织（例如骨骼）。此外，在用顺铂治疗的基底样和管腔乳腺肿瘤中，FZD1/2/7阳性细胞富含化疗耐药细胞，并且TcdBFBD与顺铂在抑制这两种肿瘤类型方面具有强烈的协同作用。这些数据证明了窄谱Wnt信号抑制剂在治疗乳腺癌中的治疗价值。版权所有：© 2023 He et al.这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。
Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.Copyright: © 2023 He et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.