Targeted inhibition of Wnt signaling with a < i > Clostridioides difficile < /i > toxin B fragment suppresses breast cancer tumor growth

by 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 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 ofC.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. T...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research