德国慕尼黑工业大学Roland Rad小组的一项最新研究提出了疾病模型资源揭示了组织特异性癌症进化的核心原则。相关论文于2026年2月25日发表在《自然》杂志上。

据悉，癌基因（如KRAS）在其致癌潜能、遗传相互作用和表型效应方面显示出显著的组织特异性，但潜在的决定因素在很大程度上仍未得到解决。为了解决这些问题，该团队开发了小鼠癌症细胞系图谱，这是一个广泛实用的图谱，涵盖了广泛实体的590个综合表征模型（www.mcca.tum.de）。基于该平台、人类队列和小鼠的比较和功能研究确定了KRAS引发的癌症组织特异性进化的核心原则。

首先，该团队发现突变体KRAS剂量增加通过等位基因失衡产生细胞类型特异性效应，定义其跨实体的时间，如胰腺癌起始期间剂量敏感的发育重编程。其次，课题组强调了组织和阶段特异性进化要求，如肠道分化阻断，如何选择KRAS协同改变。第三，该研究团队确定了上下文依赖的上位性KRAS-肿瘤抑制因子相互作用，并表明相互剂量敏感性决定了癌症基因改变的实体特异性模式，解释了它们的频率、合子性和获得时间。这些发现强调了内在和获得性决定因素如何指导不同组织的癌症进化，具有可预测的分子模式、时间动态和表型结果。他们的研究为癌症基因组的机制理解提供了重大进展。

附：英文原文

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

Author: Mueller, Sebastian, de Andrade Krtzig, Niklas, Tschurtschenthaler, Markus, Silva, Miguel G., Thordsen, Chiara, Trozzo, Riccardo, Simon, Perrine, Saab, Frederic, Kaltenbacher, Thorsten, Zukowska, Magdalena, Lucarelli, Daniele, llinger, Rupert, Griger, Joscha, Gro, Nina, Groll, Tanja, Lprich, Jessica, Zaurito, Antonio E., Schmig, Linus R., Bugter, Jeroen M., Brthel, Stefanie, Falcomat, Chiara, Strong, Alexander, Brandt, Cordelia, Najajreh, Mulham, Papargyriou, Aristeidis, Maresch, Roman, Collins, Katharina A. N., Sailer, David, Schneeweis, Christian, Burger, Sebastian, Frhlich, Lisa M., Klement, Christine, Belka, Alexander, Montero, Juan J., Jungwirth, Ute, Reichert, Maximilian, Moser, Markus, Neumann, Jens, Vassiliou, George, Cadianos, Juan, Varela, Ignacio, Marr, Carsten, Alonso, Daniel F., Lollini, Pier-Luigi, Zhao, Jean, Chesler, Louis, Isacke, Clare M.

Issue&Volume: 2026-02-25

Abstract: 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.

DOI: 10.1038/s41586-026-10187-2

Source: https://www.nature.com/articles/s41586-026-10187-2