The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences. Beijing, 100101, China; University of Chinese Academy of Sciences. Beijing, 100049, China.
The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University. Tianjin, 300071, China; CNBG-Nankai University Joint Research and Development Center, Tianjin, 300071, China.
Cancer Lett. 2022 Aug 1;540:215725. doi: 10.1016/j.canlet.2022.215725. Epub 2022 May 10.
Cancer stem cells (CSCs) are a subpopulation of cancer cells that drive tumour progression and metastasis. Anti-CSC strategies represent new targets for cancer therapies. However, CSCs are highly plastic and heterogeneous, making validation and targeting difficult without bona fide markers that define their identity, especially in a clinical setting. Here, we report that a leucine-rich repeat containing G protein-coupled receptor 4 (LGR4) cooperates with CD44 and PrPc; the latter contributes significantly to metastatic capacity and defines the stemness characteristics of colorectal CSCs. CD44PrPcLGR4 cells effectively developed into organoids and, when transplanted, generated orthotopic and metastatic tumours. Importantly, targeting LGR4 and PrPc with lentiviral shRNAs inhibited organoid development and the growth of orthotopic tumours by inhibiting Wnt/β-catenin signalling. Thus, our study offers a novel therapeutic strategy that simultaneously targets CSC stemness and metastatic properties.
癌症干细胞（CSCs）是驱动肿瘤进展和转移的肿瘤细胞亚群。抗 CSC 策略代表了癌症治疗的新靶点。然而，CSCs 具有高度可塑性和异质性，如果没有明确定义其身份的真正标志物，验证和靶向治疗就会变得困难，尤其是在临床环境中。在这里，我们报告富含亮氨酸重复序列的 G 蛋白偶联受体 4（LGR4）与 CD44 和 PrPc 合作；后者对转移能力有重要贡献，并定义了结直肠 CSCs 的干性特征。CD44PrPcLGR4 细胞有效地发育成类器官，并且当移植时，生成了原位和转移性肿瘤。重要的是，用慢病毒 shRNAs 靶向 LGR4 和 PrPc 通过抑制 Wnt/β-catenin 信号通路抑制了类器官的发育和原位肿瘤的生长。因此，我们的研究提供了一种新的治疗策略，该策略同时针对 CSC 的干性和转移性特性。
