Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany.
Division of Translational Cancer Research, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.
Nat Commun. 2023 May 8;14(1):2642. doi: 10.1038/s41467-023-38171-8.
Cell-selective proteomics is a powerful emerging concept to study heterocellular processes in tissues. However, its high potential to identify non-cell-autonomous disease mechanisms and biomarkers has been hindered by low proteome coverage. Here, we address this limitation and devise a comprehensive azidonorleucine labeling, click chemistry enrichment, and mass spectrometry-based proteomics and secretomics strategy to dissect aberrant signals in pancreatic ductal adenocarcinoma (PDAC). Our in-depth co-culture and in vivo analyses cover more than 10,000 cancer cell-derived proteins and reveal systematic differences between molecular PDAC subtypes. Secreted proteins, such as chemokines and EMT-promoting matrisome proteins, associated with distinct macrophage polarization and tumor stromal composition, differentiate classical and mesenchymal PDAC. Intriguingly, more than 1,600 cancer cell-derived proteins including cytokines and pre-metastatic niche formation-associated factors in mouse serum reflect tumor activity in circulation. Our findings highlight how cell-selective proteomics can accelerate the discovery of diagnostic markers and therapeutic targets in cancer.
细胞选择性蛋白质组学是研究组织中异细胞过程的一种强大的新兴概念。然而，其识别非细胞自主疾病机制和生物标志物的高潜力受到低蛋白质组覆盖率的限制。在这里，我们解决了这一限制，并设计了一种全面的叠氮正亮氨酸标记、点击化学富集和基于质谱的蛋白质组学和分泌组学策略，以剖析胰腺导管腺癌 (PDAC) 中的异常信号。我们深入的共培养和体内分析涵盖了超过 10000 种癌细胞衍生蛋白，并揭示了分子 PDAC 亚型之间的系统差异。分泌蛋白，如趋化因子和 EMT 促进的基质蛋白，与不同的巨噬细胞极化和肿瘤基质组成相关，区分经典和间充质 PDAC。有趣的是，超过 1600 种癌细胞衍生蛋白，包括细胞因子和与预转移生态位形成相关的因子，在小鼠血清中反映了循环中的肿瘤活性。我们的研究结果强调了细胞选择性蛋白质组学如何加速癌症诊断标志物和治疗靶点的发现。
