Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations

Abstract Standard therapy of osteosarcoma (OS) and Ewing sarcoma (EW) rests on cytotoxic regimes, which are largely unsuccessful in advanced patients. Preclinical models are needed to break this impasse. A panel of patient-derived xenografts (PDX) was established by implantation of fresh, surgically...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Patrizia Nanni, Lorena Landuzzi, Maria Cristina Manara, Alberto Righi, Giordano Nicoletti, Camilla Cristalli, Michela Pasello, Alessandro Parra, Marianna Carrabotta, Manuela Ferracin, Arianna Palladini, Marianna L. Ianzano, Veronica Giusti, Francesca Ruzzi, Mauro Magnani, Davide Maria Donati, Piero Picci, Pier-Luigi Lollini, Katia Scotlandi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/520fd06572ac4ed78a2083b0e3a1fa0d
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:520fd06572ac4ed78a2083b0e3a1fa0d
record_format	dspace
spelling	oai:doaj.org-article:520fd06572ac4ed78a2083b0e3a1fa0d2021-12-02T16:08:43ZBone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations10.1038/s41598-019-48634-y2045-2322https://doaj.org/article/520fd06572ac4ed78a2083b0e3a1fa0d2019-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-48634-yhttps://doaj.org/toc/2045-2322Abstract Standard therapy of osteosarcoma (OS) and Ewing sarcoma (EW) rests on cytotoxic regimes, which are largely unsuccessful in advanced patients. Preclinical models are needed to break this impasse. A panel of patient-derived xenografts (PDX) was established by implantation of fresh, surgically resected osteosarcoma (OS) and Ewing sarcoma (EW) in NSG mice. Engraftment was obtained in 22 of 61 OS (36%) and 7 of 29 EW (24%). The success rate in establishing primary cell cultures from OS was lower than the percentage of PDX engraftment in mice, whereas the reverse was observed for EW; the implementation of both in vivo and in vitro seeding increased the proportion of patients yielding at least one workable model. The establishment of in vitro cultures from PDX was highly efficient in both tumor types, reaching 100% for EW. Morphological and immunohistochemical (SATB2, P-glycoprotein 1, CD99, caveolin 1) studies and gene expression profiling showed a remarkable similarity between patient’s tumor and PDX, which was maintained over several passages in mice, whereas cell cultures displayed a lower correlation with human samples. Genes differentially expressed between OS original tumor and PDX mostly belonged to leuykocyte-specific pathways, as human infiltrate is gradually replaced by murine leukocytes during growth in mice. In EW, which contained scant infiltrates, no gene was differentially expressed between the original tumor and the PDX. A novel therapeutic combination of anti-CD99 diabody C7 and irinotecan was tested against two EW PDX; both drugs inhibited PDX growth, the addition of anti-CD99 was beneficial when chemotherapy alone was less effective. The panel of OS and EW PDX faithfully mirrored morphologic and genetic features of bone sarcomas, representing reliable models to test therapeutic approaches.Patrizia NanniLorena LanduzziMaria Cristina ManaraAlberto RighiGiordano NicolettiCamilla CristalliMichela PaselloAlessandro ParraMarianna CarrabottaManuela FerracinArianna PalladiniMarianna L. IanzanoVeronica GiustiFrancesca RuzziMauro MagnaniDavide Maria DonatiPiero PicciPier-Luigi LolliniKatia ScotlandiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-12 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Patrizia Nanni Lorena Landuzzi Maria Cristina Manara Alberto Righi Giordano Nicoletti Camilla Cristalli Michela Pasello Alessandro Parra Marianna Carrabotta Manuela Ferracin Arianna Palladini Marianna L. Ianzano Veronica Giusti Francesca Ruzzi Mauro Magnani Davide Maria Donati Piero Picci Pier-Luigi Lollini Katia Scotlandi Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations
description	Abstract Standard therapy of osteosarcoma (OS) and Ewing sarcoma (EW) rests on cytotoxic regimes, which are largely unsuccessful in advanced patients. Preclinical models are needed to break this impasse. A panel of patient-derived xenografts (PDX) was established by implantation of fresh, surgically resected osteosarcoma (OS) and Ewing sarcoma (EW) in NSG mice. Engraftment was obtained in 22 of 61 OS (36%) and 7 of 29 EW (24%). The success rate in establishing primary cell cultures from OS was lower than the percentage of PDX engraftment in mice, whereas the reverse was observed for EW; the implementation of both in vivo and in vitro seeding increased the proportion of patients yielding at least one workable model. The establishment of in vitro cultures from PDX was highly efficient in both tumor types, reaching 100% for EW. Morphological and immunohistochemical (SATB2, P-glycoprotein 1, CD99, caveolin 1) studies and gene expression profiling showed a remarkable similarity between patient’s tumor and PDX, which was maintained over several passages in mice, whereas cell cultures displayed a lower correlation with human samples. Genes differentially expressed between OS original tumor and PDX mostly belonged to leuykocyte-specific pathways, as human infiltrate is gradually replaced by murine leukocytes during growth in mice. In EW, which contained scant infiltrates, no gene was differentially expressed between the original tumor and the PDX. A novel therapeutic combination of anti-CD99 diabody C7 and irinotecan was tested against two EW PDX; both drugs inhibited PDX growth, the addition of anti-CD99 was beneficial when chemotherapy alone was less effective. The panel of OS and EW PDX faithfully mirrored morphologic and genetic features of bone sarcomas, representing reliable models to test therapeutic approaches.
format	article
author	Patrizia Nanni Lorena Landuzzi Maria Cristina Manara Alberto Righi Giordano Nicoletti Camilla Cristalli Michela Pasello Alessandro Parra Marianna Carrabotta Manuela Ferracin Arianna Palladini Marianna L. Ianzano Veronica Giusti Francesca Ruzzi Mauro Magnani Davide Maria Donati Piero Picci Pier-Luigi Lollini Katia Scotlandi
author_facet	Patrizia Nanni Lorena Landuzzi Maria Cristina Manara Alberto Righi Giordano Nicoletti Camilla Cristalli Michela Pasello Alessandro Parra Marianna Carrabotta Manuela Ferracin Arianna Palladini Marianna L. Ianzano Veronica Giusti Francesca Ruzzi Mauro Magnani Davide Maria Donati Piero Picci Pier-Luigi Lollini Katia Scotlandi
author_sort	Patrizia Nanni
title	Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations
title_short	Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations
title_full	Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations
title_fullStr	Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations
title_full_unstemmed	Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations
title_sort	bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/520fd06572ac4ed78a2083b0e3a1fa0d
work_keys_str_mv	AT patriziananni bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT lorenalanduzzi bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT mariacristinamanara bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT albertorighi bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT giordanonicoletti bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT camillacristalli bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT michelapasello bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT alessandroparra bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT mariannacarrabotta bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT manuelaferracin bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT ariannapalladini bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT mariannalianzano bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT veronicagiusti bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT francescaruzzi bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT mauromagnani bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT davidemariadonati bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT pieropicci bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT pierluigilollini bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations AT katiascotlandi bonesarcomapatientderivedxenograftsarefaithfulandstablepreclinicalmodelsformolecularandtherapeuticinvestigations
_version_	1718384467363495936

Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations

Ejemplares similares