Cancer Research Program. CIBERONC. Institut Mar d'Investigacions Mèdiques, Hospital del Mar, Doctor Aiguader 88, 08003, Barcelona, Spain.
Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
Nat Commun. 2018 Jul 31;9(1):2992. doi: 10.1038/s41467-018-05385-0.
Delta ligands regulate Notch signaling in normal intestinal stem cells, while Jagged1 activates Notch in intestinal adenomas carrying active β-catenin. We used the Apc mouse model, tumor spheroid cultures, and patient-derived orthoxenografts to address this divergent ligand-dependent Notch function and its implication in disease. We found that intestinal-specific Jag1 deletion or antibody targeting Jag1 prevents tumor initiation in mice. Addiction to Jag1 is concomitant with the absence of Manic Fringe (MFNG) in adenoma cells, and its ectopic expression reverts Jag1 dependence. In 239 human colorectal cancer patient samples, MFNG imposes a negative correlation between Jag1 and Notch, being high Jag1 in the absence of MFNG predictive of poor prognosis. Jag1 antibody treatment reduces patient-derived tumor orthoxenograft growth without affecting normal intestinal mucosa. Our data provide an explanation to Jag1 dependence in cancer, and reveal that Jag1-Notch1 interference provides therapeutic benefit in a subset of colorectal cancer and FAP syndrome patients.
Delta 配体在正常肠干细胞中调节 Notch 信号，而 Jagged1 在携带活跃 β-catenin 的肠腺瘤中激活 Notch。我们使用 Apc 小鼠模型、肿瘤球体培养物和患者来源的异种移植物来解决这种不同的配体依赖性 Notch 功能及其在疾病中的意义。我们发现，肠道特异性 Jag1 缺失或 Jag1 抗体靶向治疗可预防小鼠肿瘤的发生。Jag1 的成瘾伴随着腺瘤细胞中 Manic Fringe（MFNG）的缺失，其异位表达可逆转 Jag1 的依赖性。在 239 名结直肠癌患者样本中，MFNG 在 Jag1 和 Notch 之间施加了负相关关系，在缺乏 MFNG 的情况下 Jag1 高表达预示着预后不良。Jag1 抗体治疗可减少患者来源的肿瘤异种移植物的生长，而不影响正常的肠黏膜。我们的数据为癌症中 Jag1 依赖性提供了一种解释，并揭示了 Jag1-Notch1 干扰在结直肠癌和 FAP 综合征患者的亚组中提供治疗益处。
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