Huang Phillips Y, Kandyba Eve, Jabouille Arnaud, Sjolund Jonas, Kumar Atul, Halliwill Kyle, McCreery Melissa, DelRosario Reyno, Kang Hio Chung, Wong Christine E, Seibler Jost, Beuger Vincent, Pellegrino Maurizio, Sciambi Adam, Eastburn Dennis J, Balmain Allan
Helen Diller Family Comprehensive Cancer Center University of California, San Francisco, San Francisco, California, USA.
Genome Institute of Singapore, Singapore.
Nat Genet. 2017 Nov;49(11):1624-1632. doi: 10.1038/ng.3957. Epub 2017 Sep 25.
The G-protein-coupled receptors LGR4, LGR5 and LGR6 are Wnt signaling mediators, but their functions in squamous cell carcinoma (SCC) are unclear. Using lineage tracing in Lgr5-EGFP-CreERT2/Rosa26-Tomato and Lgr6-EGFP-CreERT2/Rosa26-Tomato reporter mice, we demonstrate that Lgr6, but not Lgr5, acts as an epithelial stem cell marker in SCCs in vivo. We identify, by single-molecule in situ hybridization and cell sorting, rare cells positive for Lgr6 expression in immortalized keratinocytes and show that their frequency increases in advanced SCCs. Lgr6 expression is enriched in cells with stem cell characteristics, and Lgr6 downregulation in vivo causes increased epidermal proliferation with expanded lineage tracing from epidermal stem cells positive for Lgr6 expression. Surprisingly, mice with germline knockout of Lgr6 are predisposed to SCC development, through a mechanism that includes compensatory upregulation of Lgr5. These data provide a model for human patients with germline loss-of-function mutations in Wnt pathway genes, including RSPO1 or LGR4, who show increased susceptibility to squamous tumor development.
G蛋白偶联受体LGR4、LGR5和LGR6是Wnt信号传导介质，但其在鳞状细胞癌（SCC）中的功能尚不清楚。利用Lgr5-EGFP-CreERT2/Rosa26-Tomato和Lgr6-EGFP-CreERT2/Rosa26-Tomato报告基因小鼠进行谱系追踪，我们证明在体内SCC中，Lgr6而非Lgr5可作为上皮干细胞标志物。通过单分子原位杂交和细胞分选，我们在永生化角质形成细胞中鉴定出罕见的Lgr6表达阳性细胞，并表明其频率在晚期SCC中增加。Lgr6表达在具有干细胞特征的细胞中富集，体内Lgr6下调会导致表皮增殖增加，Lgr6表达阳性的表皮干细胞的谱系追踪范围扩大。令人惊讶的是，Lgr6生殖系敲除的小鼠易患SCC，其机制包括Lgr5的代偿性上调。这些数据为Wnt通路基因（包括RSPO1或LGR4）发生生殖系功能丧失突变的人类患者提供了一个模型，这些患者对鳞状肿瘤发生的易感性增加。
