Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer
Fumagalli, Arianna; Oost, Koen C.; Kester, Lennart; Morgner, Jessica; Bornes, Laura; Bruens, Lotte; Spaargaren, Lisa; Azkanaz, Maria; Schelfhorst, Tim; Beerling, Evelyne; Heinz, Maria C.; Postrach, Daniel; Seinstra, Danielle; Sieuwerts, Anieta M.; Martens, John W.M.; van der Elst, Stefan; van Baalen, Martijn; Bhowmick, Debajit; Vrisekoop, Nienke; Ellenbroek, Saskia I.J.; Suijkerbuijk, Saskia J.E.; Snippert, Hugo J.; van Rheenen, Jacco
(2020) Cell stem cell, volume 26, issue 4, pp. 569 - 578.e7
(Article)
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
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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, Molecular Medicine, Genetics, Cell Biology
ISSN: 1934-5909
Publisher: Cell Press
Note: Funding Information: We thank Anko de Graaff and the Hubrecht Imaging Centre and Amalie Dick for technical support with imaging. We thank members of the van Rheenen group for critically reading the manuscript, Life Science Editors for editing this manuscript, and Frederic J. de Sauvage for sharing the Lgr5-DTR-GFP mouse. This work was financially supported by Dutch Cancer Society Fellowship BUIT-2013-5847 (to S.J.E.S.), European Molecular Biology Organization (EMBO) fellowship ALTF 202-2016 (to J.M.), the Netherlands Organization of Scientific Research (NWO) (Veni grant 863.15.011 to S.I.J.E.), CancerGenomics.nl (to J.v.R., A.M.S., and J.W.M.M.), European Research Council Grant CANCER-RECURRENCE 648804 (to J.v.R.), the Doctor Josef Steiner Foundation (to J.v.R.), and the European Union ’s Horizon 2020 research and innovation program under Marie Skłodowska-Curie grant agreement 642866 (both to J.v.R.). Funding Information: We thank Anko de Graaff and the Hubrecht Imaging Centre and Amalie Dick for technical support with imaging. We thank members of the van Rheenen group for critically reading the manuscript, Life Science Editors for editing this manuscript, and Frederic J. de Sauvage for sharing the Lgr5-DTR-GFP mouse. This work was financially supported by Dutch Cancer Society Fellowship BUIT-2013-5847 (to S.J.E.S.), European Molecular Biology Organization (EMBO) fellowship ALTF 202-2016 (to J.M.), the Netherlands Organization of Scientific Research (NWO) (Veni grant 863.15.011 to S.I.J.E.), CancerGenomics.nl (to J.v.R. A.M.S. and J.W.M.M.), European Research Council Grant CANCER-RECURRENCE 648804 (to J.v.R.), the Doctor Josef Steiner Foundation (to J.v.R.), and the European Union's Horizon 2020 research and innovation program under Marie Sk?odowska-Curie grant agreement 642866 (both to J.v.R.). A.F. performed the experiments. K.C.O. performed part of the revision experiments with the help of M.A. E.B. and S.J.E.S. L.S. helped with the in vivo DT experiments. L. Bruens, L. Bornes, and D.S. helped with the sample preparation of the fluorescence-activated cell sorting (FACS) experiments. L.K. analyzed the single-cell sequencing data. J.M. performed the hydrogel-based assay. D.P. performed the in vitro DT cleaved caspase-3 assay. T.S. S.v.d.E. M.v.B. and D.B. operated the FACS. A.M.S. and J.W.M.M. contributed knowledge and reagents. K.C.O. and M.C.H. provided the human organoid line. Experiments were designed with the help of N.V. and H.J.S. J.v.R. together with A.F. designed the experiments and supervised the study. A.F. S.I.J.E. and J.v.R. wrote the manuscript, and the manuscript was approved by all authors. The authors declare no competing interests. Publisher Copyright: © 2020 The Authors
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