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Browsing by Author "Kopper, Oded"
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Item Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth(Public Library of Science, 2023-11-09) 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.; Jin, Rongsheng; Clevers, Hans; Xiang, Dongxi; Li, Zhe; Dong, Min; Anatomy, Cell Biology and Physiology, School of MedicineWnt 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.