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.

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Keywords cancer stem cells, circulating tumor cells, colorectal cancer, intravital microscopy, Lgr5, metastasis, microenvironment, plasticity
Persistent URL dx.doi.org/10.1016/j.stem.2020.02.008, hdl.handle.net/1765/126199
Journal Cell Stem Cell
Citation
Fumagalli, A. (Arianna), Oost, K.C. (Koen C.), Kester, L. (Lennart), Morgner, J. (Jessica), Bornes, L. (Laura), Bruens, L. (Lotte), … van Rheenen, J. (Jacco). (2020). Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer. Cell Stem Cell, 26(4), 569–578. doi:10.1016/j.stem.2020.02.008