Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth.
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-F...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-11-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3002353 |
| _version_ | 1827400198185287680 |
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| author | 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 Jin Hans Clevers Dongxi Xiang Zhe Li Min Dong |
| author_facet | 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 Jin Hans Clevers Dongxi Xiang Zhe Li Min Dong |
| author_sort | Aina He |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-08T19:58:31Z |
| format | Article |
| id | doaj.art-c1f3079f1d4342a0a3d6ba9ffe231f87 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-03-08T19:58:31Z |
| publishDate | 2023-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-c1f3079f1d4342a0a3d6ba9ffe231f872023-12-24T05:31:23ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852023-11-012111e300235310.1371/journal.pbio.3002353Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth.Aina HeSonghai TianOded KopperDaniel J HoranPeng ChenRoderick T BronsonRen ShengHao WuLufei SuiKun ZhouLiang TaoQuan WuYujing HuangZan ShenSen HanXueqing ChenHong ChenXi HeAlexander G RoblingRongsheng JinHans CleversDongxi XiangZhe LiMin DongWnt 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.https://doi.org/10.1371/journal.pbio.3002353 |
| spellingShingle | 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 Jin Hans Clevers Dongxi Xiang Zhe Li Min Dong Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth. PLoS Biology |
| title | Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth. |
| title_full | Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth. |
| title_fullStr | Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth. |
| title_full_unstemmed | Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth. |
| title_short | Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth. |
| title_sort | targeted inhibition of wnt signaling with a clostridioides difficile toxin b fragment suppresses breast cancer tumor growth |
| url | https://doi.org/10.1371/journal.pbio.3002353 |
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