A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer

Felipe de Sousa e Melo, Antonina V. Kurtova, Jonathan M. Harnoss, Noelyn Kljavin, Joerg D. Hoeck, Jeffrey Hung, Jeffrey Eastham Anderson, Elaine E. Storm, Zora Modrusan, Hartmut Koeppen, Gerrit J. P. Dijkgraaf, Robert Piskol and Frederic J. de Sauvage ()
Additional contact information
Felipe de Sousa e Melo: Molecular Oncology, Genentech
Antonina V. Kurtova: Molecular Oncology, Genentech
Jonathan M. Harnoss: Cancer Immunology, Genentech
Noelyn Kljavin: Molecular Oncology, Genentech
Joerg D. Hoeck: Molecular Oncology, Genentech
Jeffrey Hung: Research Pathology, Genentech
Jeffrey Eastham Anderson: Research Pathology, Genentech
Elaine E. Storm: Molecular Oncology, Genentech
Zora Modrusan: Molecular Biology, Genentech
Hartmut Koeppen: Research Pathology, Genentech
Gerrit J. P. Dijkgraaf: Molecular Oncology, Genentech
Robert Piskol: Bioinformatics and Computational Biology, Genentech
Frederic J. de Sauvage: Molecular Oncology, Genentech

Nature, 2017, vol. 543, issue 7647, 676-680

Abstract: Abstract Cancer stem cells (CSCs) have been hypothesized to represent the driving force behind tumour progression and metastasis, making them attractive cancer targets. However, conclusive experimental evidence for their functional relevance is still lacking for most malignancies. Here we show that the leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) identifies intestinal CSCs in mouse tumours engineered to recapitulate the clinical progression of human colorectal cancer. We demonstrate that selective Lgr5+ cell ablation restricts primary tumour growth, but does not result in tumour regression. Instead, tumours are maintained by proliferative Lgr5− cells that continuously attempt to replenish the Lgr5+ CSC pool, leading to rapid re-initiation of tumour growth upon treatment cessation. Notably, CSCs are critical for the formation and maintenance of liver metastasis derived from colorectal cancers. Together, our data highlight distinct CSC dependencies for primary versus metastasic tumour growth, and suggest that targeting CSCs may represent a therapeutic opportunity for managing metastatic disease.

Date: 2017
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DOI: 10.1038/nature21713

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