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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - Aug 21 2019

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Molecular Models
Heterografts
Sarcoma
Bone and Bones
Osteosarcoma
Therapeutics
irinotecan
Ewing's Sarcoma
Caveolin 1
Neoplasms
Primary Cell Culture
Gene Expression Profiling
Growth
Genes
Leukocytes
Cell Culture Techniques

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Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations. / Nanni, Patrizia; Landuzzi, Lorena; Manara, Maria Cristina; Righi, Alberto; Nicoletti, Giordano; Cristalli, Camilla; Pasello, Michela; Parra, Alessandro; Carrabotta, Marianna; Ferracin, Manuela; Palladini, Arianna; Ianzano, Marianna L; Giusti, Veronica; Ruzzi, Francesca; Magnani, Mauro; Donati, Davide Maria; Picci, Piero; Lollini, Pier-Luigi; Scotlandi, Katia.

In: Scientific Reports, Vol. 9, No. 1, 21.08.2019, p. 1-12.

Research output: Contribution to journalArticle

Nanni, Patrizia ; Landuzzi, Lorena ; Manara, Maria Cristina ; Righi, Alberto ; Nicoletti, Giordano ; Cristalli, Camilla ; Pasello, Michela ; Parra, Alessandro ; Carrabotta, Marianna ; Ferracin, Manuela ; Palladini, Arianna ; Ianzano, Marianna L ; Giusti, Veronica ; Ruzzi, Francesca ; Magnani, Mauro ; Donati, Davide Maria ; Picci, Piero ; Lollini, Pier-Luigi ; Scotlandi, Katia. / Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations. In: Scientific Reports. 2019 ; Vol. 9, No. 1. pp. 1-12.
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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.",
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AU - Nanni, Patrizia

AU - Landuzzi, Lorena

AU - Manara, Maria Cristina

AU - Righi, Alberto

AU - Nicoletti, Giordano

AU - Cristalli, Camilla

AU - Pasello, Michela

AU - Parra, Alessandro

AU - Carrabotta, Marianna

AU - Ferracin, Manuela

AU - Palladini, Arianna

AU - Ianzano, Marianna L

AU - Giusti, Veronica

AU - Ruzzi, Francesca

AU - Magnani, Mauro

AU - Donati, Davide Maria

AU - Picci, Piero

AU - Lollini, Pier-Luigi

AU - Scotlandi, Katia

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N2 - 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.

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