Xu Chaojie, Dong Ying, Pei Dongchen, Zhang Xintao, Han Xiaohong, Cao Congcong, Wu Baorui, Lv Changning, Kang Zhengjun, Zhou Liqun, Liu Yuchen, Yao Lin
Department of Urology, Peking University First Hospital, Peking University, Beijing, China.
Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen University, Shenzhen, China.
Int J Surg. 2025 Mar 1;111(3):2735-2751. doi: 10.1097/JS9.0000000000002270.
In the evolving field of precision oncology, the synthesis of gene circuits that specifically target cancer cells while preserving normal tissue marks a significant breakthrough. However, traditional approaches typically concentrate on single-gene targets, lacking the directed recognition and control among the intricate networks of signaling pathways. Our study presents a synthetic gene circuit, the Logic "AND" Gate Dual-Target Genetic Circuit (LAG-DTGC), which integrates multiple signals to achieve comprehensive reprogramming of various signaling pathways in bladder cancer (BC) cells. This circuit's development hinged on detailed bioinformatics analysis, pinpointing more unique biomarkers with similar expression pattern in BC. LAG-DTGC is engineered to selectively activate in cells where these biomarkers are abnormally expressed. Its precision and the remodeling cell behavior capability are further enhanced by incorporating a logic "AND" gate, triggering the circuit only in the presence of these aberrant cancer-specific biomarkers. LAG-DTGC exhibits an extraordinary ability to reprogram cancer cell signaling pathways, turning the cells' own mechanisms against them for therapeutic effect. This work highlights the potential of synthetic biology in developing precise, less toxic treatments for BC. The LAG-DTGC represents a promising new paradigm in cancer therapy.
在不断发展的精准肿瘤学领域，能够特异性靶向癌细胞同时保护正常组织的基因回路的合成是一项重大突破。然而，传统方法通常专注于单基因靶点，在复杂的信号通路网络中缺乏定向识别和控制能力。我们的研究提出了一种合成基因回路，即逻辑“与”门双靶点遗传回路（LAG-DTGC），它整合多种信号以实现对膀胱癌细胞（BC）中各种信号通路的全面重编程。该回路的开发依赖于详细的生物信息学分析，以确定在BC中具有相似表达模式的更多独特生物标志物。LAG-DTGC经过设计，可在这些生物标志物异常表达的细胞中选择性激活。通过加入逻辑“与”门，只有在存在这些异常的癌症特异性生物标志物时才触发该回路，从而进一步提高了其精准度和重塑细胞行为的能力。LAG-DTGC展现出非凡的重编程癌细胞信号通路的能力，利用细胞自身机制来对抗它们以达到治疗效果。这项工作凸显了合成生物学在开发针对BC的精准、低毒治疗方法方面的潜力。LAG-DTGC代表了癌症治疗中一种有前景的新范式。
