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

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 JinHans Clevers, Dongxi Xiang, Zhe Li, Min Dong

Research output: Contribution to journal/periodicalArticleScientificpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)e3002353
JournalPLoS Biology
Volume21
Issue number11
DOIs
Publication statusPublished - Nov 2023

Keywords

  • Humans
  • Animals
  • Mice
  • Female
  • Wnt Signaling Pathway
  • Breast Neoplasms/metabolism
  • Bacterial Toxins/metabolism
  • Clostridioides difficile/metabolism
  • Cisplatin
  • Mammary Neoplasms, Animal

Fingerprint

Dive into the research topics of 'Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth'. Together they form a unique fingerprint.

Cite this