title: A distinct role for Lgr5+stem cells in primary and metastatic colon cancer.
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.
authors.affiliation: Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Felipe
authors.initials: F
authors.lastname: de Sousa e Melo
authors.affiliation: Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Antonina V
authors.initials: AV
authors.lastname: Kurtova
authors.affiliation: Cancer Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Harnoss
authors.affiliation: Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Noelyn
authors.initials: N
authors.lastname: Kljavin
authors.affiliation: Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Joerg D
authors.initials: JD
authors.lastname: Hoeck
authors.affiliation: Research Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hung
authors.affiliation: Research Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jeffrey Eastham
authors.initials: JE
authors.lastname: Anderson
authors.affiliation: Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Elaine E
authors.initials: EE
authors.lastname: Storm
authors.affiliation: Molecular Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Research Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.affiliation: Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Gerrit J P
authors.initials: GJ
authors.lastname: Dijkgraaf
authors.affiliation: Bioinformatics and Computational Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Piskol
authors.affiliation: Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007279:Injections, Subcutaneous; D007422:Intestines / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009940:Organoids / Q000473:pathology / Q000637:transplantation; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled