PO.BCS01.13 · 生物信息与计算
化疗对癌细胞结构的重塑
Remodeling of cancer cell architecture by chemotherapy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
化疗如何重塑肿瘤细胞——以及这些变化如何影响耐药性等结局——在很大程度上仍不清楚。在此，我们对肿瘤亚细胞组织及其被化疗重组的情况进行了多模态、全局性的表征。我们使用自监督学习来编码四种正交数据模态中的蛋白质坐标：全蛋白质组尺寸排阻色谱分级（在使用顺铂或伏立诺他治疗前后）、天然状态免疫荧光成像、亲和纯化，以及覆盖7,579种蛋白质的一级序列信息。这一整合图谱解析了174个亚细胞组分，涵盖从蛋白质复合物到细胞器的分子组装体，尺寸范围约为10-9至10-5 nm。58个组分在治疗后经历了显著重塑，重现了已知的作用机制，并揭示了此前未被认识的通路改变，如细胞骨架组织和代谢重编程。我们使用全基因组CRISPR敲除药物敏感性分析系统地验证了这些“化疗响应组装体”，识别出哪些组装体赋予药物敏感性还是耐药性。经化疗重塑的组分作为预测治疗响应的癌症突变的汇聚点——包括那些参与同源重组修复、染色质重塑和双链断裂修复的突变。
查看英文原文 English abstract
How chemotherapy reshapes tumor cells-and how these changes influence outcomes such as drug resistance-remains largely unclear. Here, we present a multimodal, global characterization of tumor subcellular organization and its reorganization by chemotherapy. We use self-supervised learning to encode protein coordinates across four orthogonal data modalities: proteome-wide size-exclusion chromatography fractionation (before and after treatment with cisplatin or vorinostat), native-state immunofluorescence imaging, affinity purification, and primary sequence information covering 7,579 proteins. This integrated map resolves 174 subcellular components, spanning molecular assemblies from protein complexes to organelles across a size range of ~10-9 to10-5nm. 58 components undergo significant remodeling upon treatment, recapitulating known mechanisms of action and revealing previously unrecognized alterations in pathways such as cytoskeletal organization and metabolic rewiring. We systematically validate these “chemotherapy-response assemblies” using genome-wide CRISPR knockout drug-sensitivity profiling, identifying which assemblies confer drug sensitivity versus resistance. Chemotherapy-remodeled components serve as convergence points for cancer mutations that predict therapeutic response-including those involved in homologous recombination repair, chromatin remodeling, and double-strand break repair.
利益披露 Disclosure
G. Qian, None.