Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth
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 (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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 09, 2023
- Source ID
- 10.1371/journal.pbio.3002353
Entities
People
- Aina He
- Alexander G. Robling
- Daniel J. Horan
- Dongxi Xiang
- Hans Clevers
- Hao Wu
- Hong Chen
- Kun Zhou
- Liang Tao
- Lufei Sui
- Min Dong
- Oded Kopper
- Peng Chen
- Quan Wu
- Ren Sheng
- Roderick T. Bronson
- Rongsheng Jin
- Sen Han
- Songhai Tian
- Xi He
- Xueqing Chen
- Yujing Huang
- Zan Shen
- Zhe Li
Organizations
- Burroughs Wellcome Fund
- National Natural Science Foundation of China
- Natural Science Foundation of Shanghai
- St. Baldrick's Foundation
- United States Department of Defense