Multi-omic Dissection of Oncogenically Active Epiproteomes Identifies Drivers of Proliferative and Invasive Breast Tumors
Multi-omic Dissection of Oncogenically Active Epiproteomes Identifies Drivers of Proliferative and Invasive Breast Tumors
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致癌活性表观蛋白质组的多组学剖析鉴定出增殖性和侵袭性乳腺肿瘤的驱动因子
DOI：
10.1016/j.isci.2019.07.001
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发表时间：
2019-07-26
期刊：
影响因子：
5.8
通讯作者：
Chen, Xian
中科院分区：
文献类型：
--
作者：
Wrobel, John A.;Xie, Ling;Chen, Xian
增生性和侵袭性乳腺肿瘤在个体患者中异质性发展，在确定精确、有效治疗的新的可用药靶点方面提出了重大挑战。在这里，我们提出了一种功能多组学方法，相互作用相关的多组学异常模式(IC-MAP)，它剖析了肿瘤内的异质性，并原位识别了驱动增殖性和侵袭性肿瘤的多组学异常的致癌后果。首先，我们对乳腺癌(BC)患者组织进行基于染色质活性的化学蛋白质组学(CHAC)实验，以确定表现为致癌活性蛋白的遗传/转录改变。CHAC使用了一种生物素化的小分子探针，它特定地结合到致癌活性的组蛋白甲基转移酶G9a上，从而能够对代表组织中主要BC亚型的G9a相互作用的蛋白质复合体进行分选/浓缩。其次，利用患者的转录/基因组数据，我们回溯性地鉴定了一些显示个性化IC图谱的G9a相互作用因子编码基因。我们的IC-MAP发现既代表了新的诊断/预后标记物，用于识别患有不可治愈的转移性疾病的患者亚组，也代表了创建个性化治疗策略的目标。
Proliferative and invasive breast tumors evolve heterogeneously in individual patients, posing significant challenges in identifying new druggable targets for precision, effective therapy. Here we present a functional multi-omics method, interaction-Correlated Multi-omic Aberration Patterning (iC-MAP), which dissects intra-tumor heterogeneity and identifies in situ the oncogenic consequences of multi-omics aberrations that drive proliferative and invasive tumors. First, we perform chromatin activity-based chemoproteomics (ChaC) experiments on breast cancer (BC) patient tissues to identify genetic/transcriptomic alterations that manifest as oncogenically active proteins. ChaC employs a biotinylated small molecule probe that specifically binds to the oncogenically active histone methyltransferase G9a, enabling sorting/enrichment of a G9a-interacting protein complex that represents the predominant BC subtype in a tissue. Second, using patient transcriptomic/genomic data, we retrospectively identified some G9a interactor-encoding genes that showed individualized iC-MAP. Our iC-MAP findings represent both new diagnostic/prognostic markers to identify patient subsets with incurable metastatic disease and targets to create individualized therapeutic strategies.