| Title: |
Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth |
| Authors: |
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; CMM; Cancer; Hubrecht Institute with UMC |
| Publication Year: |
2023 |
| Subject Terms: |
General Neuroscience; General Biochemistry,Genetics and Molecular Biology; General Immunology and Microbiology; General Agricultural and Biological Sciences |
| Description: |
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 Type: |
article in journal/newspaper |
| File Description: |
text/plain |
| Language: |
English |
| ISSN: |
1544-9173 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/451214 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/451214 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.54E7A541 |
| Database: |
BASE |