1. Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth.
- Author
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He, Aina, Tian, Songhai, Kopper, Oded, Horan, Daniel J., Chen, Peng, Bronson, Roderick T., Sheng, Ren, Wu, Hao, Sui, Lufei, Zhou, Kun, Tao, Liang, Wu, Quan, Huang, Yujing, Shen, Zan, Han, Sen, Chen, Xueqing, Chen, Hong, He, Xi, Robling, Alexander G., and Jin, Rongsheng
- Subjects
WNT signal transduction ,CLOSTRIDIOIDES difficile ,TUMOR growth ,BREAST cancer ,BREAST tumors ,BREAST ,BACTERIAL toxins - Abstract
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 (TcdB
FBD ), 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. Wnt signaling is transmitted via ten homologous Frizzled receptors (FZD1-10) in humans, complicating the therapeutic use of inhibitors due to side-effects. This study shows that a bacterial toxin fragment can be used as a tool to specifically inhibit Wnt signaling mediated by a subset of Frizzed receptors (FZD1, 2, 7), with potential for cancer treatment. [ABSTRACT FROM AUTHOR]- Published
- 2023
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