The MET oncogene transforms human primary bone-derived cells into osteosarcomas by targeting committed osteo-progenitors

Nadia Dani, Martina Olivero, Katia Mareschi, Marjan Maria Van Duist, Silvia Miretti, Sara Cuvertino, Salvatore Patanè, Raffaele Calogero, Riccardo Ferracini, Katia Scotlandi, Franca Fagioli, Maria Flavia Di Renzo

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1322-1334
Number of pages13
JournalJournal of Bone and Mineral Research
Volume27
Issue number6
DOIs
Publication statusPublished - Jun 2012

Fingerprint

Osteosarcoma
Oncogenes
Bone and Bones
Mesenchymal Stromal Cells
Clone Cells
Chondrocytes
Adipocytes
Osteoblasts
Cell Differentiation
Phosphotransferases
Stem Cells
Genome

Keywords

  • HEPATOCYTE GROWTH FACTOR RECEPTOR
  • MET ONCOGENE
  • OSTEO-PROGENITOR
  • OSTEOSARCOMA
  • OSTEOSARCOMAGENESIS

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

The MET oncogene transforms human primary bone-derived cells into osteosarcomas by targeting committed osteo-progenitors. / Dani, Nadia; Olivero, Martina; Mareschi, Katia; Van Duist, Marjan Maria; Miretti, Silvia; Cuvertino, Sara; Patanè, Salvatore; Calogero, Raffaele; Ferracini, Riccardo; Scotlandi, Katia; Fagioli, Franca; Di Renzo, Maria Flavia.

In: Journal of Bone and Mineral Research, Vol. 27, No. 6, 06.2012, p. 1322-1334.

Research output: Contribution to journalArticle

Dani, N, Olivero, M, Mareschi, K, Van Duist, MM, Miretti, S, Cuvertino, S, Patanè, S, Calogero, R, Ferracini, R, Scotlandi, K, Fagioli, F & Di Renzo, MF 2012, 'The MET oncogene transforms human primary bone-derived cells into osteosarcomas by targeting committed osteo-progenitors', Journal of Bone and Mineral Research, vol. 27, no. 6, pp. 1322-1334. https://doi.org/10.1002/jbmr.1578
Dani, Nadia ; Olivero, Martina ; Mareschi, Katia ; Van Duist, Marjan Maria ; Miretti, Silvia ; Cuvertino, Sara ; Patanè, Salvatore ; Calogero, Raffaele ; Ferracini, Riccardo ; Scotlandi, Katia ; Fagioli, Franca ; Di Renzo, Maria Flavia. / The MET oncogene transforms human primary bone-derived cells into osteosarcomas by targeting committed osteo-progenitors. In: Journal of Bone and Mineral Research. 2012 ; Vol. 27, No. 6. pp. 1322-1334.
@article{6767ec076d5d4e8cabfb0d75190303d4,
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.",
keywords = "HEPATOCYTE GROWTH FACTOR RECEPTOR, MET ONCOGENE, OSTEO-PROGENITOR, OSTEOSARCOMA, OSTEOSARCOMAGENESIS",
author = "Nadia Dani and Martina Olivero and Katia Mareschi and {Van Duist}, {Marjan Maria} and Silvia Miretti and Sara Cuvertino and Salvatore Patan{\`e} and Raffaele Calogero and Riccardo Ferracini and Katia Scotlandi and Franca Fagioli and {Di Renzo}, {Maria Flavia}",
year = "2012",
month = "6",
doi = "10.1002/jbmr.1578",
language = "English",
volume = "27",
pages = "1322--1334",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - The MET oncogene transforms human primary bone-derived cells into osteosarcomas by targeting committed osteo-progenitors

AU - Dani, Nadia

AU - Olivero, Martina

AU - Mareschi, Katia

AU - Van Duist, Marjan Maria

AU - Miretti, Silvia

AU - Cuvertino, Sara

AU - Patanè, Salvatore

AU - Calogero, Raffaele

AU - Ferracini, Riccardo

AU - Scotlandi, Katia

AU - Fagioli, Franca

AU - Di Renzo, Maria Flavia

PY - 2012/6

Y1 - 2012/6

N2 - 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.

AB - 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.

KW - HEPATOCYTE GROWTH FACTOR RECEPTOR

KW - MET ONCOGENE

KW - OSTEO-PROGENITOR

KW - OSTEOSARCOMA

KW - OSTEOSARCOMAGENESIS

UR - http://www.scopus.com/inward/record.url?scp=84861325260&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861325260&partnerID=8YFLogxK

U2 - 10.1002/jbmr.1578

DO - 10.1002/jbmr.1578

M3 - Article

C2 - 22367914

AN - SCOPUS:84861325260

VL - 27

SP - 1322

EP - 1334

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 6

ER -