title: The MET oncogene transforms human primary bone-derived cells into osteosarcomas by targeting committed osteo-progenitors.
abstract: The MET oncogene is aberrantly overexpressed in human osteosarcomas. We have previously converted primary cultures of human bone-derived cells into osteosarcoma cells by overexpressing MET. To determine whether MET transforms mesenchymal stem cells or committed progenitor cells, here we characterize distinct MET overexpressing osteosarcoma (MET-OS) clones using genome-wide expression profiling, cytometric analysis, and functional assays. All the MET-OS clones consistently display mesenchymal and stemness markers, but not most of the mesenchymal–stem cell-specific markers. Conversely, the MET-OS clones express genes characteristic of early osteoblastic differentiation phases, but not those of late phases. Profiling of mesenchymal stem cells induced to differentiate along osteoblast, adipocyte, and chondrocyte lineages confirms that MET-OS cells are similar to cells at an initial phase of osteoblastic differentiation. Accordingly, MET-OS cells cannot differentiate into adipocytes or chondrocytes, but can partially differentiate into osteogenic-matrix-producing cells. Moreover, in vitro MET-OS cells form self-renewing spheres enriched in cells that can initiate tumors in vivo. MET kinase inhibition abrogates the self-renewal capacity of MET-OS cells and allows them to progress toward osteoblastic differentiation. These data show that MET initiates the transformation of a cell population that has features of osteo-progenitors and suggest that MET regulates self-renewal and lineage differentiation of osteosarcoma cells.
authors.affiliation: Laboratory of Cancer Genetics, Department of Oncological Sciences University of Torino School of Medicine, Turin, Italy
authors.forename: Nadia
authors.initials: N
authors.lastname: Dani
authors.forename: Martina
authors.initials: M
authors.lastname: Olivero
authors.forename: Katia
authors.initials: K
authors.lastname: Mareschi
authors.forename: Marjan Maria
authors.initials: MM
authors.lastname: van Duist
authors.forename: Silvia
authors.initials: S
authors.lastname: Miretti
authors.forename: Sara
authors.initials: S
authors.lastname: Cuvertino
authors.forename: Salvatore
authors.initials: S
authors.lastname: Patané
authors.forename: Raffaele
authors.initials: R
authors.lastname: Calogero
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ferracini
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
authors.forename: Franca
authors.initials: F
authors.lastname: Fagioli
authors.forename: Maria Flavia
authors.initials: MF
authors.lastname: Di Renzo
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D002999:Clone Cells; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology*; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D019859:Proto-Oncogene Proteins c-met