Department of Biochemistry, McMaster University, Hamilton, ON, Canada.
Department of Biochemistry, McMaster University, Hamilton, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
Cell Chem Biol. 2023 Jul 20;30(7):780-794.e8. doi: 10.1016/j.chembiol.2023.06.004. Epub 2023 Jun 27.
Overlapping principles of embryonic and tumor biology have been described, with recent multi-omics campaigns uncovering shared molecular profiles between human pluripotent stem cells (hPSCs) and adult tumors. Here, using a chemical genomic approach, we provide biological evidence that early germ layer fate decisions of hPSCs reveal targets of human cancers. Single-cell deconstruction of hPSCs-defined subsets that share transcriptional patterns with transformed adult tissues. Chemical screening using a unique germ layer specification assay for hPSCs identified drugs that enriched for compounds that selectively suppressed the growth of patient-derived tumors corresponding exclusively to their germ layer origin. Transcriptional response of hPSCs to germ layer inducing drugs could be used to identify targets capable of regulating hPSC specification as well as inhibiting adult tumors. Our study demonstrates properties of adult tumors converge with hPSCs drug induced differentiation in a germ layer specific manner, thereby expanding our understanding of cancer stemness and pluripotency.
胚胎生物学和肿瘤生物学之间存在重叠的原则，最近的多组学研究揭示了人类多能干细胞（hPSC）和成人肿瘤之间存在共同的分子特征。在这里，我们使用化学基因组学方法，提供了生物学证据，表明 hPSC 的早期胚层命运决定揭示了人类癌症的靶点。单细胞解构 hPSC 定义的亚群，这些亚群与转化的成人组织具有转录模式。使用独特的 hPSC 胚层特化测定法进行化学筛选，鉴定出了药物，这些药物富集了专门抑制仅与其胚层起源相对应的患者来源肿瘤生长的化合物。hPSC 对胚层诱导药物的转录反应可用于鉴定能够调节 hPSC 特化以及抑制成人肿瘤的靶标。我们的研究表明，成体肿瘤的特性与 hPSC 药物诱导的分化以胚层特异性的方式趋同，从而扩展了我们对癌症干性和多能性的理解。
