{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T05:25:39Z","timestamp":1775798739296,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T00:00:00Z","timestamp":1563321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004099","name":"Ligue Contre le Cancer","doi-asserted-by":"publisher","award":["Osteomics"],"award-info":[{"award-number":["Osteomics"]}],"id":[{"id":"10.13039\/501100004099","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Etoile de Martin","award":["Osteomics"],"award-info":[{"award-number":["Osteomics"]}]},{"name":"SFCE","award":["Osteomics"],"award-info":[{"award-number":["Osteomics"]}]},{"name":"F\u00e9d\u00e9ration Enfants et Sant\u00e9","award":["Osteomics"],"award-info":[{"award-number":["Osteomics"]}]},{"name":"Une main Vers l'Espoir association","award":["Osteomics"],"award-info":[{"award-number":["Osteomics"]}]},{"DOI":"10.13039\/501100019370","name":"Foundation For Science and Technology","doi-asserted-by":"publisher","award":["SFRH\/BD\/89137\/2012"],"award-info":[{"award-number":["SFRH\/BD\/89137\/2012"]}],"id":[{"id":"10.13039\/501100019370","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Osteosarcoma, the most common bone malignancy with a peak incidence at adolescence, had no survival improvement since decades. Persistent problems are chemo-resistance and metastatic spread. We developed in-vitro osteosarcoma models resistant to chemotherapy and in-vivo bioluminescent orthotopic cell-derived-xenografts (CDX). Continuous increasing drug concentration cultures in-vitro resulted in five methotrexate (MTX)-resistant and one doxorubicin (DOXO)-resistant cell lines. Resistance persisted after drug removal except for MG-63. Different resistance mechanisms were identified, affecting drug transport and action mechanisms specific to methotrexate (RFC\/SCL19A1 decrease, DHFR up-regulation) for MTX-resistant lines, or a multi-drug phenomenon (PgP up-regulation) for HOS-R\/DOXO. Differential analysis of copy number abnormalities (aCGH) and gene expression (RNAseq) revealed changes of several chromosomic regions translated at transcriptomic level depending on drug and cell line, as well as different pathways implicated in invasive and metastatic potential (e.g., Fas, Metalloproteinases) and immunity (enrichment in HLA cluster genes in 6p21.3) in HOS-R\/DOXO. Resistant-CDX models (HOS-R\/MTX, HOS-R\/DOXO and Saos-2-B-R\/MTX) injected intratibially into NSG mice behaved as their parental counterpart at primary tumor site; however, they exhibited a slower growth rate and lower metastatic spread, although they retained resistance and CGH main characteristics without drug pressure. These models represent valuable tools to explore resistance mechanisms and new therapies in osteosarcoma.<\/jats:p>","DOI":"10.3390\/cancers11070997","type":"journal-article","created":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T11:25:12Z","timestamp":1563362712000},"page":"997","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["In-Vitro and In-Vivo Establishment and Characterization of Bioluminescent Orthotopic Chemotherapy-Resistant Human Osteosarcoma Models in NSG Mice"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1498-603X","authenticated-orcid":false,"given":"Maria Eug\u00e9nia","family":"Marques da Costa","sequence":"first","affiliation":[{"name":"National Centre for Scientific Research (CNRS), UMR8203, Gustave Roussy, 94805 Villejuif, France"},{"name":"University of Paris-Saclay, 91190 Saint-Aubin, France"},{"name":"University of Paris Sud, 91400 Orsay, France"},{"name":"Department of Biology, Centre for Environmental and Marine Studies (CESAM), University of Aveiro, 3810 Aveiro, Portugal"}]},{"given":"Antonin","family":"Marchais","sequence":"additional","affiliation":[{"name":"National Centre for Scientific Research (CNRS), UMR8203, Gustave Roussy, 94805 Villejuif, France"},{"name":"University of Paris-Saclay, 91190 Saint-Aubin, France"},{"name":"University of Paris Sud, 91400 Orsay, France"}]},{"given":"Anne","family":"Gomez-Brouchet","sequence":"additional","affiliation":[{"name":"IUCT-Oncopole, CHU and University of Toulouse, Pathology department, 31100 Toulouse, France"},{"name":"National Centre for Scientific Research (CNRS), UMR5089, 31077 Toulouse, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2720-7664","authenticated-orcid":false,"given":"Bastien","family":"Job","sequence":"additional","affiliation":[{"name":"National Institute for Health and Medical Research (INSERM), US23, Gustave Roussy, 94805 Villejuif, France"}]},{"given":"No\u00e9mie","family":"Assoun","sequence":"additional","affiliation":[{"name":"National Centre for Scientific Research (CNRS), UMR8203, Gustave Roussy, 94805 Villejuif, France"},{"name":"University of Paris-Saclay, 91190 Saint-Aubin, France"},{"name":"University of Paris Sud, 91400 Orsay, France"}]},{"given":"Estelle","family":"Daudigeos-Dubus","sequence":"additional","affiliation":[{"name":"National Centre for Scientific Research (CNRS), UMR8203, Gustave Roussy, 94805 Villejuif, France"},{"name":"University of Paris-Saclay, 91190 Saint-Aubin, France"},{"name":"University of Paris Sud, 91400 Orsay, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3050-6155","authenticated-orcid":false,"given":"Olivia","family":"Fromigu\u00e9","sequence":"additional","affiliation":[{"name":"University of Paris Sud, 91400 Orsay, France"},{"name":"National Institute for Health and Medical Research (INSERM), UMR981, Gustave Roussy, 94805 Villejuif, France"}]},{"given":"Concei\u00e7\u00e3o","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Sciences, University of Porto, 4000 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4361-3643","authenticated-orcid":false,"given":"Birgit","family":"Geoerger","sequence":"additional","affiliation":[{"name":"National Centre for Scientific Research (CNRS), UMR8203, Gustave Roussy, 94805 Villejuif, France"},{"name":"University of Paris-Saclay, 91190 Saint-Aubin, France"},{"name":"University of Paris Sud, 91400 Orsay, France"},{"name":"Department of Oncology for Child and Adolescent, Gustave Roussy, 94805 Villejuif, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1827-8903","authenticated-orcid":false,"given":"Nathalie","family":"Gaspar","sequence":"additional","affiliation":[{"name":"National Centre for Scientific Research (CNRS), UMR8203, Gustave Roussy, 94805 Villejuif, France"},{"name":"University of Paris-Saclay, 91190 Saint-Aubin, France"},{"name":"University of Paris Sud, 91400 Orsay, France"},{"name":"Department of Oncology for Child and Adolescent, Gustave Roussy, 94805 Villejuif, France"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2896","DOI":"10.1038\/bjc.2014.254","article-title":"Prevention of multidrug resistance (MDR) in osteosarcoma by NSC23925","volume":"110","author":"Yang","year":"2014","journal-title":"Br. 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