System Biology Institute, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; MCGD Program, Yale University, 333 Cedar Street, New Haven, CT 06510, USA.
System Biology Institute, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA; Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA; Center for Cancer Systems Biology, Integrated Science & Technology Center, 850 West Campus Drive, West Haven, CT 06516, USA.
Cell Syst. 2019 Feb 27;8(2):136-151.e7. doi: 10.1016/j.cels.2019.01.004. Epub 2019 Feb 20.
The genetic makeup of cancer cells directs oncogenesis and influences the tumor microenvironment. In this study, we massively profiled genes that functionally drive tumorigenesis using genome-scale in vivo CRISPR screens in hosts with different levels of immunocompetence. As a convergent hit from these screens, Prkar1a mutant cells are able to robustly outgrow as tumors in fully immunocompetent hosts. Functional interrogation showed that Prkar1a loss greatly altered the transcriptome and proteome involved in inflammatory and immune responses as well as extracellular protein production. Single-cell transcriptomic profiling and flow cytometry analysis mapped the tumor microenvironment of Prkar1a mutant tumors and revealed the transcriptomic alterations in host myeloid cells. Taken together, our data suggest that tumor-intrinsic mutations in Prkar1a lead to drastic alterations in the genetic program of cancer cells, thereby remodeling the tumor microenvironment.
癌细胞的基因构成指导肿瘤发生，并影响肿瘤微环境。在这项研究中，我们使用具有不同免疫能力的宿主中的全基因组规模体内 CRISPR 筛选，大规模分析了那些在功能上驱动肿瘤发生的基因。作为这些筛选的一个收敛命中，Prkar1a 突变细胞能够在完全免疫能力的宿主中作为肿瘤强劲地生长。功能询问表明，Prkar1a 的缺失极大地改变了参与炎症和免疫反应以及细胞外蛋白产生的转录组和蛋白质组。单细胞转录组谱分析和流式细胞术分析绘制了 Prkar1a 突变肿瘤的肿瘤微环境，并揭示了宿主髓样细胞中的转录组改变。总之，我们的数据表明，Prkar1a 中的肿瘤内在突变导致癌细胞遗传程序的剧烈改变，从而重塑肿瘤微环境。
