Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer

TLDR

Colorectal cancer stem cells express Lgr5 and are thought to seed metastatic disease. The study investigates the cell of origin of metastases in colorectal cancer using mouse models and human tumor xenografts. Using a mouse CRC model and human xenografts, the authors examined which cells give rise to metastases. They found that most circulating CRC cells are Lgr5−, yet metastases contain Lgr5+ CSCs, indicating that Lgr5− cells can intrinsically convert to CSCs and drive metastatic outgrowth independent of niche signals.

Abstract

Colorectal cancer stem cells (CSCs) express Lgr5 and display extensive stem cell-like multipotency and self-renewal and are thought to seed metastatic disease. Here, we used a mouse model of colorectal cancer (CRC) and human tumor xenografts to investigate the cell of origin of metastases. We found that most disseminated CRC cells in circulation were Lgr5− and formed distant metastases in which Lgr5+ CSCs appeared. This plasticity occurred independently of stemness-inducing microenvironmental factors and was indispensable for outgrowth, but not establishment, of metastases. Together, these findings show that most colorectal cancer metastases are seeded by Lgr5− cells, which display intrinsic capacity to become CSCs in a niche-independent manner and can restore epithelial hierarchies in metastatic tumors.