LGR4 cooperates with PrPc to endow the stemness of colorectal cancer stem cells contributing to tumorigenesis and liver metastasis. (1st August 2022)

• Record Type: Journal Article
• Authors: Cheng, Qi; Zheng, Hao; Li, Ming; Wang, Hongyi; Guo, Xiaoxiao; Zheng, Zhibo; Chen, Chuyan; Liu, Jinming; Zhan, Tiancheng; Li, Zhaowei; Wu, Hao; Han, Jingdong; Liu, Lei; Tang, Tieshan; Chen, Quan; Du, Lei
• Is Part Of: Cancer letters. Volume 540(2022)
• Publication Date: 2022-08-01
• Subjects: LGR4 -- Cancer stem cell -- PrPc -- Colorectal cancer -- Tumour organoid; CSC cancer stem cell -- LGR4 leucine-rich repeat containing G protein-coupled receptor 4 -- PrPc cellular prion protein -- TMA tissue micro-array -- FACS fluorescence-activated cell sorting -- IHC immunohistochemistry; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215725
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. 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/β-catenin signalling. Thus, our study offers a novel therapeutic strategy that simultaneously targets CSC stemness and metastatic properties. Highlights: LGR4 co-expresses with PrPc and enriches colorectal CSCs from patient tumours. LGR4 is a new surface marker that defines the stemness properties of CSC. Single LGR4 + CSC from patient tumours generates tumour-derived organoids. Knockdown of LGR4 and PrPc decreases organoid formation, tumour initiation and metastasis.