PO.MCB06.02 · 分子与细胞生物学
结直肠和乳腺肿瘤微环境中保守的内皮细胞特异性DNA甲基化改变
Conserved endothelial cell-specific DNA methylation alterations in colorectal and breast tumor microenvironments
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
DNA甲基化改变是公认的癌变促成因素,然而,在肿瘤微环境(TME)中,谱系特异性和细胞特异性的模式仍表征不足。我们应用一种批量DNA甲基化解卷积方法(HiTIMED),结合一种细胞类型特异性差异甲基化框架(CellDMC),以鉴定和验证结直肠癌及非肿瘤正常组织中肿瘤内皮细胞(TEC)特异性的DNA甲基化改变。我们此前在乳腺癌中鉴定了TEC特异性的DNA甲基化改变。在此,我们评估乳腺和结直肠肿瘤之间共享的内皮特异性表观遗传程序。内皮细胞作为血管生成和血管稳态的关键调控因子,常获得促进肿瘤进展的分子和结构异常。我们使用来自发现和验证框架(肿瘤n = 725;非肿瘤n = 989)的结直肠组织的全基因组规模DNA甲基化数据,鉴定出38,647个CpGs(FDR≤0.05),在发现集和验证集中均具有TEC特异性的DNA甲基化改变,对应13,249个基因。与正常组织内皮细胞相比,大多数CpGs在TEC中呈高甲基化。CpG簇映射到已知调控血管生成、内皮细胞生物学的基因、VEGF信号通路中的基因以及标志性血管生成基因集的成员。对结直肠和乳腺TME中TEC特异性甲基化改变的比较分析显示,在CpG水平上有24%的重叠,在基因水平上有81%的重叠,提示不同肿瘤类型之间存在保守的内皮特异性甲基化失调程序。在我们此前乳腺癌分析中几乎所有表达与内皮细胞比例相关的基因,也在结直肠数据集中被鉴定出来。这些发现表明,在不同的肿瘤背景下,内皮细胞重编程存在共享的表观遗传结构。正在进行的表达分析将把这些比较扩展到结直肠肿瘤中,以进一步将DNA甲基化与转录调控联系起来。总之,我们的结果证明,可以从批量肿瘤DNA甲基化谱重建高分辨率、谱系特异性的DNA甲基化景观,并确立了保守的TEC特异性表观遗传特征,对肿瘤血管生物学和精准治疗靶向具有意义。
查看英文原文 English abstract
DNA methylation alterations are well-established contributors to carcinogenesis, yet, within the tumor microenvironment (TME), lineage- and cell-specific patterns remain poorly characterized. We applied a bulk DNA methylation deconvolution approach (HiTIMED) combined with a cell-type-specific differential methylation framework (CellDMC) to identify and validate tumor endothelial cell (TEC) specific DNA methylation alterations in colorectal cancer and nontumor normal tissue. We previously identified TEC-specific DNA methylation alterations in breast cancer. Here, we evaluate the shared endothelial-specific epigenetic programs between breast and colorectal tumors. Endothelial cells, key regulators of angiogenesis and vascular homeostasis, often acquire molecular and structural abnormalities that promote tumor progression. Using genome-scale DNA methylation data from a discovery and validation framework (tumor n = 725; nontumor n = 989) of colorectal tissues, we identified 38,647 CpGs (FDR ≤ 0.05) with altered DNA methylation specific to TECs in both discovery and validation sets, corresponding to 13,249 genes. The majority of CpGs were hypermethylated in TEC compared to endothelial cells in normal tissue. Clusters of CpGs mapped to genes known to regulate angiogenesis, endothelial cell biology, genes in the VEGF signaling pathway, and members of the hallmark angiogenesis gene set. Comparative analysis of TEC-specific methylation alterations in the colorectal and breast TME showed a 24% overlap at the CpG level, and an 81% overlap at the gene level, suggesting conserved endothelial-specific methylation dysregulation programs between tumor types. Nearly all genes whose expression correlated with endothelial cell proportion in our previous breast cancer analysis were also identified in the colorectal datasets. These findings indicate a shared epigenetic architecture underlying endothelial cell reprogramming in distinct tumor contexts. Ongoing expression analyses will extend these comparisons in colorectal tumors to further link DNA methylation with transcriptional regulation. Together, our results demonstrate that high-resolution, lineage-specific DNA methylation landscapes can be reconstructed from bulk tumor DNA methylation profiles and establish conserved TEC-specific epigenetic signatures with implications for tumor vascular biology and precision therapeutic targeting.
利益披露 Disclosure
B. Karakyriakou, None.