Targeting the NOTCH2/ADAM10/TCF7L2 Axis‐Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer
Abstract Wnt/β‐catenin/transcription factor (TCF) transcriptional activity plays an integral role in colorectal cancer (CRC) carcinogenesis. However, to date, no drugs targeting this pathway are used in clinical practice owing to the undesirable and serious side effects. In this study, it is found t...
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2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202405758 |
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| author | Zhen Xiang Yiwei Wang Xiao Ma Shuzheng Song Yuanqiao He Jiamin Zhou Longhai Feng Su Yang Yibin Wu Bingran Yu Guangkai Xia Weiqi Xu Yiming Zhao Lu Wang |
| author_facet | Zhen Xiang Yiwei Wang Xiao Ma Shuzheng Song Yuanqiao He Jiamin Zhou Longhai Feng Su Yang Yibin Wu Bingran Yu Guangkai Xia Weiqi Xu Yiming Zhao Lu Wang |
| author_sort | Zhen Xiang |
| collection | DOAJ |
| description | Abstract Wnt/β‐catenin/transcription factor (TCF) transcriptional activity plays an integral role in colorectal cancer (CRC) carcinogenesis. However, to date, no drugs targeting this pathway are used in clinical practice owing to the undesirable and serious side effects. In this study, it is found that the transcriptional regulation of Wnt pathway is activated and associated with liver metastasis in CRC. Through high‐throughput screening of 24 inhibitors on 12 CRC and three colorectal organoids in this organoid living biobank, adavivint is found to exhibit anti‐tumor activity and low toxicity in colorectal organoids, independent of the canonical Wnt/β‐catenin signaling. Mechanistically, ADAM10 is screened as a target of adavivint to specifically regulate the protein expression of NOTCH2, which mediates the transcriptional regulation of the Wnt pathway. NOTCH2 not directly interact with TCF7‐like 2 (TCF7L2), a key downstream transcriptional factor of canonical Wnt/β‐catenin signaling, but directly activated the transcription of TCF7L2 and Wnt target genes, such as MYC, JUN and CCND1/2. Furthermore, use of adavivint or blockage of ADAM10/NOTCH2/TCF7L2 signaling enhances the chemosensitivity of CRC cells. Overall, this study provides a promising candidate for the development of small‐molecule inhibitors and reveals a potential therapeutic target for CRC. |
| format | Article |
| id | doaj-art-1819a0751adf44e1b6b4e75a9eeb5c98 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-1819a0751adf44e1b6b4e75a9eeb5c982025-01-20T13:04:18ZengWileyAdvanced Science2198-38442025-01-01123n/an/a10.1002/advs.202405758Targeting the NOTCH2/ADAM10/TCF7L2 Axis‐Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal CancerZhen Xiang0Yiwei Wang1Xiao Ma2Shuzheng Song3Yuanqiao He4Jiamin Zhou5Longhai Feng6Su Yang7Yibin Wu8Bingran Yu9Guangkai Xia10Weiqi Xu11Yiming Zhao12Lu Wang13Department of Hepatic Surgery Fudan University Shanghai Cancer Center 270 Dong‐An Road Shanghai 200032 ChinaDepartment of general surgery Shanghai Jiao Tong University Affiliated Sixth People's Hospital 600 Yishan Rd Shanghai 200233 P. R. ChinaFudan University Shanghai Cancer Center 270 Dong‐An Road Shanghai 200032 P. R. ChinaDepartment of Colorectal Surgery Department of General Surgery Shanghai East Hospital Tongji University School of Medicine 150 Jimo Road Shanghai 200120 P. R. ChinaCenter of Laboratory Animal Science Nanchang University No.999, Xuefu Road Nanchang 330031 P. R. ChinaDepartment of Hepatic Surgery Fudan University Shanghai Cancer Center 270 Dong‐An Road Shanghai 200032 ChinaDepartment of Colorectal Surgery The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) 1 Banshan East Road Hangzhou 310022 P. R. ChinaDepartment of Thoracic Surgery Ruijin Hospital Shanghai Jiaotong University School of Medicine 197 Ruijin 2nd Road Shanghai 200025 P. R. ChinaDepartment of Hepatic Surgery Fudan University Shanghai Cancer Center 270 Dong‐An Road Shanghai 200032 ChinaDepartment of Hepatic Surgery Fudan University Shanghai Cancer Center 270 Dong‐An Road Shanghai 200032 ChinaDepartment of general surgery Shanghai Jiao Tong University Affiliated Sixth People's Hospital 600 Yishan Rd Shanghai 200233 P. R. ChinaDepartment of Hepatic Surgery Fudan University Shanghai Cancer Center 270 Dong‐An Road Shanghai 200032 ChinaDepartment of Hepatic Surgery Fudan University Shanghai Cancer Center 270 Dong‐An Road Shanghai 200032 ChinaDepartment of Hepatic Surgery Fudan University Shanghai Cancer Center 270 Dong‐An Road Shanghai 200032 ChinaAbstract Wnt/β‐catenin/transcription factor (TCF) transcriptional activity plays an integral role in colorectal cancer (CRC) carcinogenesis. However, to date, no drugs targeting this pathway are used in clinical practice owing to the undesirable and serious side effects. In this study, it is found that the transcriptional regulation of Wnt pathway is activated and associated with liver metastasis in CRC. Through high‐throughput screening of 24 inhibitors on 12 CRC and three colorectal organoids in this organoid living biobank, adavivint is found to exhibit anti‐tumor activity and low toxicity in colorectal organoids, independent of the canonical Wnt/β‐catenin signaling. Mechanistically, ADAM10 is screened as a target of adavivint to specifically regulate the protein expression of NOTCH2, which mediates the transcriptional regulation of the Wnt pathway. NOTCH2 not directly interact with TCF7‐like 2 (TCF7L2), a key downstream transcriptional factor of canonical Wnt/β‐catenin signaling, but directly activated the transcription of TCF7L2 and Wnt target genes, such as MYC, JUN and CCND1/2. Furthermore, use of adavivint or blockage of ADAM10/NOTCH2/TCF7L2 signaling enhances the chemosensitivity of CRC cells. Overall, this study provides a promising candidate for the development of small‐molecule inhibitors and reveals a potential therapeutic target for CRC.https://doi.org/10.1002/advs.202405758ADAM10colorectal cancerliver metastasisNOTCH2organoidTCF7L2 |
| spellingShingle | Zhen Xiang Yiwei Wang Xiao Ma Shuzheng Song Yuanqiao He Jiamin Zhou Longhai Feng Su Yang Yibin Wu Bingran Yu Guangkai Xia Weiqi Xu Yiming Zhao Lu Wang Targeting the NOTCH2/ADAM10/TCF7L2 Axis‐Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer Advanced Science ADAM10 colorectal cancer liver metastasis NOTCH2 organoid TCF7L2 |
| title | Targeting the NOTCH2/ADAM10/TCF7L2 Axis‐Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer |
| title_full | Targeting the NOTCH2/ADAM10/TCF7L2 Axis‐Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer |
| title_fullStr | Targeting the NOTCH2/ADAM10/TCF7L2 Axis‐Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer |
| title_full_unstemmed | Targeting the NOTCH2/ADAM10/TCF7L2 Axis‐Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer |
| title_short | Targeting the NOTCH2/ADAM10/TCF7L2 Axis‐Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer |
| title_sort | targeting the notch2 adam10 tcf7l2 axis mediated transcriptional regulation of wnt pathway suppresses tumor growth and enhances chemosensitivity in colorectal cancer |
| topic | ADAM10 colorectal cancer liver metastasis NOTCH2 organoid TCF7L2 |
| url | https://doi.org/10.1002/advs.202405758 |
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