Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A. 2017 Jun 20;114(25):6581-6586. doi: 10.1073/pnas.1701263114. Epub 2017 Jun 12.
Identification of biomarkers and therapeutic targets is a critical goal of precision medicine. N-glycoproteins are a particularly attractive class of proteins that constitute potential cancer biomarkers and therapeutic targets for small molecules, antibodies, and cellular therapies. Using mass spectrometry (MS), we generated a compendium of 1,091 N-glycoproteins (from 40 human primary lymphomas and cell lines). Hierarchical clustering revealed distinct subtype signatures that included several subtype-specific biomarkers. Orthogonal immunological studies in 671 primary lymphoma tissue biopsies and 32 lymphoma-derived cell lines corroborated MS data. In anaplastic lymphoma kinase-positive (ALK) anaplastic large cell lymphoma (ALCL), integration of N-glycoproteomics and transcriptome sequencing revealed an ALK-regulated cytokine/receptor signaling network, including vulnerabilities corroborated by a genome-wide clustered regularly interspaced short palindromic screen. Functional targeting of IL-31 receptor β, an ALCL-enriched and ALK-regulated N-glycoprotein in this network, abrogated ALKALCL growth in vitro and in vivo. Our results highlight the utility of functional proteogenomic approaches for discovery of cancer biomarkers and therapeutic targets.
鉴定生物标志物和治疗靶点是精准医学的一个关键目标。N-糖蛋白是一类特别有吸引力的蛋白质，它们构成了小分子、抗体和细胞疗法的潜在癌症生物标志物和治疗靶点。我们使用质谱（MS）技术生成了 1091 种 N-糖蛋白（来自 40 个人类原发性淋巴瘤和细胞系）的汇编。层次聚类显示出不同的亚型特征，包括几个亚型特异性生物标志物。在 671 份原发性淋巴瘤组织活检和 32 份淋巴瘤衍生细胞系的正交免疫研究中，证实了 MS 数据的可靠性。在间变性淋巴瘤激酶阳性（ALK）间变性大细胞淋巴瘤（ALCL）中，N-糖蛋白组学和转录组测序的整合揭示了一个 ALK 调节的细胞因子/受体信号网络，包括全基因组聚类规则间隔短回文重复筛选所证实的脆弱性。在这个网络中，功能靶向白细胞介素 31 受体 β，一种 ALCL 丰富和 ALK 调节的 N-糖蛋白，在体外和体内都消除了 ALKALCL 的生长。我们的结果强调了功能蛋白质基因组学方法在发现癌症生物标志物和治疗靶点方面的实用性。
