LGR5+ colorectal cancer CSCs are dispensable for primary tumor growth due to plasticity.
Major finding: LGR5+ colorectal cancer CSCs are dispensable for primary tumor growth due to plasticity.
Concept: LGR5+ CSCs are critical for the formation and maintenance of colon cancer–derived liver metastases.
Impact: Targeting LGR5+ CSCs may suppress metastasis, but CSC plasticity may limit efficacy in primary tumors.
Self-renewing cancer stem cells (CSC) are thought to drive tumor growth in multiple malignancies and have emerged as potential therapeutic targets in cancer. However, there is insufficient experimental evidence to understand their functional role in many tumors, including colorectal cancer. De Sousa e Melo and colleagues generated a series of intestinal tumor organoid models in which LGR5+ cells could be depleted with diphtheria toxin (DT). In tumor organoid allografts, LGR5 marked the tumor-initiating cells across organoid tumors engineered to recapitulate the progression of the human disease. Depletion of LGR5+ cancer stem cells with DT resulted in tumor stasis, but not the anticipated tumor regression. When DT was removed, the tumors rapidly resumed growth and again contained LGR5+ cells, indicating a plasticity under which LGR5− cells can revert back to an LGR5+ stem cell state. LGR5+ cells were required for metastatic dissemination and maintenance, as tumors established in the liver regressed upon CSC depletion. In a related study, Shimokawa and colleagues performed lineage-tracing experiments using a CRISPR/Cas9-mediated LGR5–CreER knock-in allele to independently demonstrate that LGR5+ cells serve as CSCs in human colorectal cancer. LGR5 depletion suppressed the growth of patient-derived tumor organoids, but the tumors eventually regrew as LGR5+ cells reemerged. Further, the anti-EGFR antibody cetuximab, which is used to treat colorectal cancer and increases the number of LGR5+ cells, cooperated with CSC ablation to reduce tumor size in mice. Collectively, the results of these studies demonstrate that LGR5+ cells serve as CSCs in colorectal cancer, and suggest that the functional contribution of CSCs for tumor growth is intimately dependent on the influence of local environmental cues.