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528 results on '"He, Aina"'

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

Author

He, Aina, Tian, Songhai, Kopper, Oded, Horan, Daniel, Chen, Peng, Bronson, Roderick, 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, Jin, Rongsheng, Clevers, Hans, Xiang, Dongxi, Li, Zhe, and Dong, Min

Subjects
Humans, Animals, Mice, Female, Wnt Signaling Pathway, Breast Neoplasms, Bacterial Toxins, Clostridioides difficile, Cisplatin, Mammary Neoplasms, Animal
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.

Published
2023

49. Structural basis for recognition of frizzled proteins by Clostridium difficile toxin B

Author

Chen, Peng, Tao, Liang, Wang, Tianyu, Zhang, Jie, He, Aina, Lam, Kwok-Ho, Liu, Zheng, He, Xi, Perry, Kay, Dong, Min, and Jin, Rongsheng

Subjects
Digestive Diseases, Emerging Infectious Diseases, Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Infection, Bacterial Proteins, Bacterial Toxins, Binding Sites, Clostridioides difficile, Clostridium Infections, Crystallography, X-Ray, Fatty Acids, Frizzled Receptors, Humans, Protein Domains, Virulence Factors, Wnt Signaling Pathway, General Science & Technology
Abstract

Clostridium difficile infection is the most common cause of antibiotic-associated diarrhea in developed countries. The major virulence factor, C. difficile toxin B (TcdB), targets colonic epithelia by binding to the frizzled (FZD) family of Wnt receptors, but how TcdB recognizes FZDs is unclear. Here, we present the crystal structure of a TcdB fragment in complex with the cysteine-rich domain of human FZD2 at 2.5-angstrom resolution, which reveals an endogenous FZD-bound fatty acid acting as a co-receptor for TcdB binding. This lipid occupies the binding site for Wnt-adducted palmitoleic acid in FZDs. TcdB binding locks the lipid in place, preventing Wnt from engaging FZDs and signaling. Our findings establish a central role of fatty acids in FZD-mediated TcdB pathogenesis and suggest strategies to modulate Wnt signaling.

Published
2018

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