CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Univ. Lille, 59000, Lille, France.
Inserm, U1003-PHYCEL-Physiologie Cellulaire, Univ. Lille, 59000, Lille, France.
Biol Res. 2024 Sep 3;57(1):59. doi: 10.1186/s40659-024-00540-y.
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.
肿瘤休眠是癌细胞采用的一种抵抗机制，是癌症治疗的重大挑战，导致微小残留病（MRD）和潜在复发。尽管其具有临床重要性，但肿瘤休眠和 MRD 的机制仍不清楚。在这项研究中，我们使用两种髓样白血病和黑色素瘤的同源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。我们采用多组学方法阐明驱动 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、染色质免疫沉淀测序（ChIP-seq）、转录组和蛋白质组学研究。WES 分析显示，黑色素瘤和白血病休眠模型中的基因突变有适度重叠，而在休眠细胞中发现了大量独特的基因突变。这些独特的遗传特征表明，在 MRD 期间存在选择性压力，可能赋予了对微环境或治疗的抵抗性。CNV、组蛋白标记和转录组基因表达特征与基因本体论（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 相关的途径提供了见解。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研究相结合，揭示了休眠细胞中失调蛋白的特征，涉及最小的遗传机制参与。途径富集分析显示，代谢、分化和细胞骨架重塑过程与 MRD 有关。最后，我们鉴定了两种病理休眠细胞中 11 个差异表达的共同蛋白。
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。通过比较基因组学、转录组学、蛋白质组学和表观基因组学数据集，我们的研究提供了对微小残留病分子景观的全面理解。这些结果为进一步的研究提供了坚实的基础，并为白血病和黑色素瘤患者的靶向 MRD 治疗提供了潜在途径，强调在治疗策略中考虑遗传和非遗传因素的重要性。
