LGR5 marks targetable tumor-initiating cells in mouse liver cancer

Wanlu Cao, Meng Li, Jiaye Liu, Shaoshi Zhang, Lisanne Noordam, Monique M. A. Verstegen, Ling Wang, Buyun Ma, Shan Li, Wenshi Wang, Michiel Bolkestein, Michael Doukas, Kan Chen, Zhongren Ma, Marco Bruno, Dave Sprengers, Jaap Kwekkeboom, Luc J. W. van der Laan, Ron Smits, Maikel P. Peppelenbosch and Qiuwei Pan ()
Additional contact information
Wanlu Cao: Erasmus MC-University Medical Center
Meng Li: Erasmus MC-University Medical Center
Jiaye Liu: Erasmus MC-University Medical Center
Shaoshi Zhang: Erasmus MC-University Medical Center
Lisanne Noordam: Erasmus MC-University Medical Center
Monique M. A. Verstegen: Erasmus MC-University Medical Center
Ling Wang: Erasmus MC-University Medical Center
Buyun Ma: Erasmus MC-University Medical Center
Shan Li: Erasmus MC-University Medical Center
Wenshi Wang: Erasmus MC-University Medical Center
Michiel Bolkestein: Erasmus MC-University Medical Center
Michael Doukas: Erasmus MC-University Medical Center
Kan Chen: Erasmus MC-University Medical Center
Zhongren Ma: Northwest Minzu University
Marco Bruno: Erasmus MC-University Medical Center
Dave Sprengers: Erasmus MC-University Medical Center
Jaap Kwekkeboom: Erasmus MC-University Medical Center
Luc J. W. van der Laan: Erasmus MC-University Medical Center
Ron Smits: Erasmus MC-University Medical Center
Maikel P. Peppelenbosch: Erasmus MC-University Medical Center
Qiuwei Pan: Erasmus MC-University Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Cancer stem cells (CSCs) or tumor-initiating cells (TICs) are thought to be the main drivers for disease progression and treatment resistance across various cancer types. Identifying and targeting these rare cancer cells, however, remains challenging with respect to therapeutic benefit. Here, we report the enrichment of LGR5 expressing cells, a well-recognized stem cell marker, in mouse liver tumors, and the upregulation of LGR5 expression in human hepatocellular carcinoma. Isolated LGR5 expressing cells from mouse liver tumors are superior in initiating organoids and forming tumors upon engraftment, featuring candidate TICs. These cells are resistant to conventional treatment including sorafenib and 5-FU. Importantly, LGR5 lineage ablation significantly inhibits organoid initiation and tumor growth. The combination of LGR5 ablation with 5-FU, but not sorafenib, further augments the therapeutic efficacy in vivo. Thus, we have identified the LGR5+ compartment as an important TIC population, representing a viable therapeutic target for combating liver cancer.

Date: 2020
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DOI: 10.1038/s41467-020-15846-0

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