文章：

疾病模型资源揭示组织特异性癌症进化的核心原理

A disease model resource reveals core principles of tissue-specific cancer evolution

原文发布日期：2026-02-25

DOI: 10.1038/s41586-026-10187-2

类型: Article

开放获取: 是

英文摘要：

Oncogenes such as KRAS display marked tissue specificity in their oncogenic potential, genetic interactions and phenotypic effects, but the underlying determinants remain largely unresolved1,2,3,4,5. Here, to address these questions, we developed the Mouse Cancer Cell line Atlas, a broad-utility resource of 590 comprehensively characterized models across a wide range of entities (www.mcca.tum.de). Comparative and functional studies using this platform, human cohorts and mice identified core principles underlying tissue-specific evolution of KRAS-initiated cancers. First, we show that mutant KRAS dosage gain through allelic imbalance exerts cell-type-specific effects, defining its timing across entities, as exemplified by dosage-sensitive developmental reprogramming during pancreatic cancer initiation. Second, we highlight how tissue- and stage-specific evolutionary requirements, such as block of differentiation in the intestine, select for KRAS-collaborating alterations. Third, we identified context-dependent epistatic KRAS–tumour suppressor interactions and show that reciprocal dosage sensitivities dictate the entity-specific patterns of cancer gene alterations, explaining their frequency, zygosity and acquisition chronology. These findings highlight how intrinsic and acquired determinants instruct cancer evolution in different tissues, with predictable molecular patterns, temporal dynamics and phenotypic outcomes. Our study provides major advances towards a mechanistic understanding of cancer genomes.

摘要翻译： 

诸如KRAS等致癌基因在致癌潜能、遗传互作及表型效应中表现出显著的组织特异性，但其潜在决定因素仍未阐明¹⁻⁵。为解决这些问题，我们建立了小鼠癌细胞系图谱——一个涵盖590种跨实体瘤类型且经全面表征的广谱资源平台（www.mcca.tum.de）。通过该平台、人类队列及小鼠模型的比较功能研究，我们揭示了KRAS驱动肿瘤组织特异性演化的核心机制：第一，发现突变KRAS通过等位基因失衡实现的剂量扩增呈现细胞类型特异性效应，并决定了该事件在不同肿瘤类型中的发生时序，例如胰腺癌起始过程中剂量敏感性发育重编程现象；第二，阐明组织及时期特异性演化需求（如肠道分化阻滞）如何选择KRAS协同突变；第三，鉴定出环境依赖性KRAS-抑癌基因互作模式，证明双向剂量敏感性决定癌症基因改变的组织特异性图谱，进而解释其突变频率、合子性及获得时序。这些发现揭示了内在因素与获得性决定因子如何通过可预测的分子模式、时间动态及表型结果，指导不同组织的癌症演化进程。本研究为理解癌症基因组的机制性规律提供了重要突破。

原文链接：

A disease model resource reveals core principles of tissue-specific cancer evolution