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

Aina He, Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Writing – original draft,# 1 , 2 , 3 Songhai Tian, Conceptualization, Data curation, Formal analysis, Investigation,# 2 , 3 , 4 Oded Kopper, Investigation, 5 Daniel J. Horan, Investigation, 6 Peng Chen, Investigation, 7 Roderick T. Bronson, Investigation, 8 Ren Sheng, Investigation, 9 Hao Wu, Investigation, 10 Lufei Sui, Investigation, 10 Kun Zhou, Investigation, 10 Liang Tao, Investigation, 2 , 3 Quan Wu, Investigation, 2 , 3 , 11 Yujing Huang, Investigation, 1 Zan Shen, Investigation, 1 Sen Han, Investigation, 12 , 13 Xueqing Chen, Investigation, 12 , 13 Hong Chen, Investigation, 10 Xi He, Investigation, 9 Alexander G. Robling, Investigation, 6 Rongsheng Jin, Conceptualization, Investigation, 7 Hans Clevers, Investigation, 5 Dongxi Xiang, Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft,corresponding author 12 , 13 , 14 , 15 ,* Zhe Li, Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Resources, Supervision, Writing – original draft,corresponding author 12 , 13 ,* and Min Dong, Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Resources, Supervision, Writing – original draftcorresponding author 2 , 3 ,*

Published: 1 November 2023

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.

 

Full Access Link: PLoS biology