Department of Biology, Stanford University, Stanford, CA, USA.
Department of Neurobiology, Stanford University, Stanford, CA, USA.
Science. 2019 May 3;364(6439). doi: 10.1126/science.aat6982.
An important goal in synthetic biology is to engineer biochemical pathways to address unsolved biomedical problems. One long-standing problem in molecular medicine is the specific identification and ablation of cancer cells. Here, we describe a method, named Rewiring of Aberrant Signaling to Effector Release (RASER), in which oncogenic ErbB receptor activity, instead of being targeted for inhibition as in existing treatments, is co-opted to trigger therapeutic programs. RASER integrates ErbB activity to specifically link oncogenic states to the execution of desired outputs. A complete mathematical model of RASER and modularity in design enable rational optimization and output programming. Using RASER, we induced apoptosis and CRISPR-Cas9-mediated transcription of endogenous genes specifically in ErbB-hyperactive cancer cells. Delivery of apoptotic RASER by adeno-associated virus selectively ablated ErbB-hyperactive cancer cells while sparing ErbB-normal cells. RASER thus provides a new strategy for oncogene-specific cancer detection and treatment.
合成生物学的一个重要目标是设计生化途径来解决未解决的生物医学问题。分子医学中的一个长期问题是特异性识别和消融癌细胞。在这里，我们描述了一种名为“重排异常信号以引发效应器释放”（Rewiring of Aberrant Signaling to Effector Release，RASER）的方法，其中致癌的 ErbB 受体活性不是像现有治疗方法那样被靶向抑制，而是被用来触发治疗程序。RASER 整合了 ErbB 活性，将致癌状态与所需输出的执行特异性地联系起来。RASER 的完整数学模型和模块化设计使优化和输出编程成为可能。使用 RASER，我们在 ErbB 过度活跃的癌细胞中特异性诱导凋亡和 CRISPR-Cas9 介导的内源性基因转录。腺相关病毒传递凋亡的 RASER 选择性地消融 ErbB 过度活跃的癌细胞，而保留 ErbB 正常细胞。因此，RASER 为癌基因特异性癌症检测和治疗提供了一种新策略。
