LGR4 cooperates with PrPc to endow the stemness of colorectal cancer stem cells contributing to tumorigenesis and liver metastasis
LGR4 cooperates with PrPc to endow the stemness of colorectal cancer stem cells contributing to tumorigenesis and liver metastasis
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DOI：
10.1016/j.canlet.2022.215725
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发表时间：
2022-05-17
期刊：
影响因子：
9.7
通讯作者：
Du, Lei
中科院分区：
文献类型：
--
作者：
Cheng, Qi;Zheng, Hao;Du, Lei
癌症干细胞（CSC）是驱动肿瘤进展和转移的癌细胞亚群。抗CSC策略代表了癌症治疗的新靶点。然而，CSC是高度可塑性和异质性的，使得在没有真正的标志物来定义其身份的情况下，验证和靶向变得困难，特别是在临床环境中。在这里，我们报告了一个富含亮氨酸重复的G蛋白偶联受体4（LGR 4）与CD 44和PrPc合作;后者对转移能力有显著贡献，并定义了结直肠CSC的干性特征。CD 44（+）PrPc（+）LGR 4（+）细胞有效地发育成类器官，并且在移植时产生原位和转移性肿瘤。重要的是，用慢病毒shRNA靶向LGR 4和PrPc通过抑制Wnt/β-连环蛋白信号传导抑制类器官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，同时针对CSC的干性和转移性。
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) co -operates with CD44 and PrPc; the latter contributes significantly to metastatic capacity and defines the stemness characteristics of colorectal CSCs. CD44(+)PrPc(+)LGR4(+) 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/beta-catenin signalling. Thus, our study offers a novel therapeutic strategy that simultaneously targets CSC stemness and metastatic properties.