肿瘤休眠是癌细胞采用的一种抵抗机制，是癌症治疗中的一个重大挑战，会导致微小残留病 (MRD) 和潜在的复发。尽管其临床重要性，肿瘤休眠和 MRD 的机制仍不清楚。在这项研究中，我们采用了髓系白血病和黑色素瘤的两种同基因小鼠模型来研究与肿瘤休眠相关的遗传、表观遗传、转录组和蛋白质特征。我们使用多组学方法来阐明驱动 MRD 的分子机制并确定潜在的治疗靶点。我们进行了深入的组学分析，包括全外显子组测序 (WES)、拷贝数变异 (CNV) 分析、染色质免疫沉淀和测序 (ChIP) -seq）、转录组和蛋白质组研究。 WES 分析显示，黑色素瘤和白血病休眠模型之间的基因突变存在一定程度的重叠，其中大量突变基因仅在休眠细胞中发现。这些独特的基因特征表明 MRD 过程中存在选择性压力，可能会产生对微环境或疗法的抵抗力。 CNV、组蛋白标记和转录组基因表达特征与基因本体 (GO) 富集分析相结合，突出了突变基因的潜在功能作用，为与 MRD 相关的通路提供了见解。此外，我们通过公共数据集将“小鼠 MRD 基因”图谱与相应的人类疾病进行了比较，并根据疾病进展突出了共同特征。蛋白质组学分析与多组学遗传学研究相结合，揭示了休眠细胞中的失调蛋白质特征，而遗传机制的参与最少。通路富集分析揭示了 MRD 涉及的代谢、分化和细胞骨架重塑过程。最后，我们鉴定了两种病理的休眠细胞中差异表达的 11 种常见蛋白质。我们的研究强调了肿瘤休眠的复杂性，涉及遗传和非遗传因素。通过比较基因组、转录组、蛋白质组和表观基因组数据集，我们的研究提供了对微小残留病分子景观的全面了解。这些结果为即将进行的研究奠定了坚实的基础，并为推进白血病和黑色素瘤患者的靶向 MRD 治疗提供了潜在途径，强调了在治疗策略中考虑遗传和非遗传因素的重要性。© 2024。作者。

Tumour dormancy, a resistance mechanism employed by cancer cells, is a significant challenge in cancer treatment, contributing to minimal residual disease (MRD) and potential relapse. Despite its clinical importance, the mechanisms underlying tumour dormancy and MRD remain unclear. In this study, we employed two syngeneic murine models of myeloid leukemia and melanoma to investigate the genetic, epigenetic, transcriptomic and protein signatures associated with tumour dormancy. We used a multiomics approach to elucidate the molecular mechanisms driving MRD and identify potential therapeutic targets.We conducted an in-depth omics analysis encompassing whole-exome sequencing (WES), copy number variation (CNV) analysis, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome and proteome investigations. WES analysis revealed a modest overlap of gene mutations between melanoma and leukemia dormancy models, with a significant number of mutated genes found exclusively in dormant cells. These exclusive genetic signatures suggest selective pressure during MRD, potentially conferring resistance to the microenvironment or therapies. CNV, histone marks and transcriptomic gene expression signatures combined with Gene Ontology (GO) enrichment analysis highlighted the potential functional roles of the mutated genes, providing insights into the pathways associated with MRD. In addition, we compared "murine MRD genes" profiles to the corresponding human disease through public datasets and highlighted common features according to disease progression. Proteomic analysis combined with multi-omics genetic investigations, revealed a dysregulated proteins signature in dormant cells with minimal genetic mechanism involvement. Pathway enrichment analysis revealed the metabolic, differentiation and cytoskeletal remodeling processes involved in MRD. Finally, we identified 11 common proteins differentially expressed in dormant cells from both pathologies.Our study underscores the complexity of tumour dormancy, implicating both genetic and nongenetic factors. By comparing genomic, transcriptomic, proteomic, and epigenomic datasets, our study provides a comprehensive understanding of the molecular landscape of minimal residual disease. These results provide a robust foundation for forthcoming investigations and offer potential avenues for the advancement of targeted MRD therapies in leukemia and melanoma patients, emphasizing the importance of considering both genetic and nongenetic factors in treatment strategies.© 2024. The Author(s).