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

TY - JOUR

T1 - Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth

AU - He, Aina

AU - Tian, Songhai

AU - Kopper, Oded

AU - Horan, Daniel J

AU - Chen, Peng

AU - Bronson, Roderick T

AU - Sheng, Ren

AU - Wu, Hao

AU - Sui, Lufei

AU - Zhou, Kun

AU - Tao, Liang

AU - Wu, Quan

AU - Huang, Yujing

AU - Shen, Zan

AU - Han, Sen

AU - Chen, Xueqing

AU - Chen, Hong

AU - He, Xi

AU - Robling, Alexander G

AU - Jin, Rongsheng

AU - Clevers, Hans

AU - Xiang, Dongxi

AU - Li, Zhe

AU - Dong, Min

N1 - Copyright: © 2023 He et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2023/11

Y1 - 2023/11

N2 - 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.

AB - 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.

KW - Humans

KW - Animals

KW - Mice

KW - Female

KW - Wnt Signaling Pathway

KW - Breast Neoplasms/metabolism

KW - Bacterial Toxins/metabolism

KW - Clostridioides difficile/metabolism

KW - Cisplatin

KW - Mammary Neoplasms, Animal

U2 - 10.1371/journal.pbio.3002353

DO - 10.1371/journal.pbio.3002353

M3 - Article

C2 - 37943878

SN - 1544-9173

VL - 21

SP - e3002353

JO - PLoS Biology

JF - PLoS Biology

IS - 11

ER -