Visualization and targeting of LGR5+ human colon cancer stem cells

The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5 + colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen-inducible Cre knock-in allele of LGR5 reveal the self-renewal and differentiation capacity of LGR5 + tumour cells. Selective ablation of LGR5 + CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5 + CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5 + CSCs and contributing to tumour regrowth after LGR5 + CSC ablation. We also show that combined chemotherapy potentiates targeting of LGR5 + CSCs. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer. LGR5 + cells in human colorectal cancer tissue xenografted into mice act as cancer stem cells, and differentiated cancer cells can revert to cancer stem cells and express LGR5 after ablation of existing LGR5 + cells. Probing the plasticity of cancer stem cells Cancer stem cells are thought to maintain tumour growth by self-renewal but their clonal dynamics and plasticity in humans are not well understood. Mariko Shimokava et al . study the role of Lgr5 + cancer stem cells in patient-derived organoids that are transplanted into mice to monitor tumour growth. Through lineage tracing, they find that tumour growth is fuelled by Lgr5 + cells, which either self-renew or differentiate into KRT20 + cells. Unexpectedly, ablation of Lgr5 + cells only leads to temporary tumour regression and tumour growth resumes driven by KRT20 + cells that exhibit compensatory proliferation and conversion to Lgr5 + cells. They also find that targeting tumours with an anti-EGFR antibody that upregulates Lgr5 acts in synergy with Lgr5 + cell ablation to block tumour growth. These findings shed new light on cell plasticity within a hierarchical cancer stem cell model and suggest new therapeutic strategies.