Xiang Zhen, Wang Yiwei, Ma Xiao, Song Shuzheng, He Yuanqiao, Zhou Jiamin, Feng Longhai, Yang Su, Wu Yibin, Yu Bingran, Xia Guangkai, Xu Weiqi, Zhao Yiming, Wang Lu
Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China.
Department of general surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai, 200233, P. R. China.
Adv Sci (Weinh). 2025 Jan;12(3):e2405758. doi: 10.1002/advs.202405758. Epub 2024 Nov 27.
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.
Wnt/β-连环蛋白/转录因子（TCF）转录活性在结直肠癌（CRC）致癌过程中起着不可或缺的作用。然而，迄今为止，由于不良和严重的副作用，尚无针对该途径的药物用于临床实践。在本研究中，发现Wnt途径的转录调控被激活并与CRC中的肝转移相关。通过在这个类器官生物样本库中对12种CRC和三种结直肠类器官进行24种抑制剂的高通量筛选，发现阿达维文特在结直肠类器官中表现出抗肿瘤活性和低毒性，且不依赖于经典的Wnt/β-连环蛋白信号传导。从机制上讲，ADAM10被筛选为阿达维文特的靶点，以特异性调节NOTCH2的蛋白表达，NOTCH2介导Wnt途径的转录调控。NOTCH2不直接与经典Wnt/β-连环蛋白信号传导的关键下游转录因子TCF7样2（TCF7L2）相互作用，但直接激活TCF7L2和Wnt靶基因（如MYC、JUN和CCND1/2）的转录。此外，使用阿达维文特或阻断ADAM10/NOTCH2/TCF7L2信号传导可增强CRC细胞的化学敏感性。总体而言，本研究为小分子抑制剂的开发提供了一个有前景的候选药物，并揭示了CRC的一个潜在治疗靶点。
