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The differentiation stage of p53-Rb-deficient bone marrow mesenchymal stem cells imposes the phenotype of in vivo sarcoma development

Abstract

Increasing evidence suggests that mesenchymal stem/stromal cells (MSCs) carrying specific mutations are at the origin of some sarcomas. We have reported that the deficiency of p53 alone or in combination with Rb (Rb−/− p53−/−) in adipose-derived MSCs (ASCs) promotes leiomyosarcoma-like tumors in vivo. Here, we hypothesized that the source of MSCs and/or the cell differentiation stage could determine the phenotype of sarcoma development. To investigate whether there is a link between the source of MSCs and sarcoma phenotype, we generated p53−/− and Rb−/−p53−/− MSCs from bone marrow (BM-MSCs). Both genotypes of BM-MSCs initiated leiomyosarcoma formation similar to p53−/− and Rb−/−p53−/− ASCs. In addition, gene expression profiling revealed transcriptome similarities between p53- or Rb-p53-deficient BM-MSCs/ASCs and muscle-associated sarcomagenesis. These data suggest that the tissue source of MSC does not seem to determine the development of a particular sarcoma phenotype. To analyze whether the differentiation stage defines the sarcoma phenotype, BM-MSCs and ASCs were induced to differentiate toward the osteogenic lineage, and both p53 and Rb were excised using Cre-expressing adenovectors at different stages along osteogenic differentiation. Regardless the level of osteogenic commitment, the inactivation of Rb and p53 in BM-MSC-derived, but not in ASC-derived, osteogenic progenitors gave rise to osteosarcoma-like tumors, which could be serially transplanted. This indicates that the osteogenic differentiation stage of BM-MSCs imposes the phenotype of in vivo sarcoma development, and that BM-MSC-derived osteogenic progenitors rather than undifferentiated BM-MSCs, undifferentiated ASCs or ASC-derived osteogenic progenitors, represent the cell of origin for osteosarcoma development.

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Acknowledgements

We thank the Andalusian Platform of Bioinformatics (PAB; University of Málaga) for providing access to IPA software. This work was supported by the Instituto de Salud Carlos III/FEDER (PI10/00449 to PM, CP11/00024—Miguet Servet Program—to RRo and RTICC RD12/0036/0015); the Junta de Andalucía/FEDER (P08-CTS-3678 to PM), the MINECO (Fondo Especial del Estado para Dinamización de la Economía y Empleo PLE-2009-0111 to PM and SAF2010-15106 to MLT), The Spanish Association Against Cancer (Junta Provincial de Albacete-CI110023 to PM and Junta Provincial de Granada to RRo), Health Canada (H4084-112281 to PM, RRo and MR-M) and Obra Social Cajastur-IUOPA. RRu was supported by a fellowship of the ISCIII/FEDER.

Author contributions: RRu: conception and design, collection and/or of assembly data, data analysis, interpretation and manuscript writing. SG-G: collection of data, data analysis and interpretation IG-A, AIS-C, AL, MR-M and MLT: data analysis and interpretation. PM and RRo: conception and design, financial support, data analysis and interpretation and manuscript writing. The manuscript has been seen and approved by all authors.

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Correspondence to P Menendez or R Rodriguez.

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Rubio, R., Gutierrez-Aranda, I., Sáez-Castillo, A. et al. The differentiation stage of p53-Rb-deficient bone marrow mesenchymal stem cells imposes the phenotype of in vivo sarcoma development. Oncogene 32, 4970–4980 (2013). https://doi.org/10.1038/onc.2012.507

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