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Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need
Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) can be considered as a spectrum of the same disease entity, representing one of the most common adult soft tissue sarcoma (STS) of the extremities. While MFS is rarely metastasizing, it shows an extremely high rate of multiple fre...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138892/ https://www.ncbi.nlm.nih.gov/pubmed/37108089 http://dx.doi.org/10.3390/ijms24086926 |
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author | Vanni, Silvia Fausti, Valentina Fonzi, Eugenio Liverani, Chiara Miserocchi, Giacomo Spadazzi, Chiara Cocchi, Claudia Calabrese, Chiara Gurrieri, Lorena Riva, Nada Recine, Federica Casadei, Roberto Pieri, Federica Guerrieri, Ania Naila Serra, Massimo Ibrahim, Toni Mercatali, Laura De Vita, Alessandro |
author_facet | Vanni, Silvia Fausti, Valentina Fonzi, Eugenio Liverani, Chiara Miserocchi, Giacomo Spadazzi, Chiara Cocchi, Claudia Calabrese, Chiara Gurrieri, Lorena Riva, Nada Recine, Federica Casadei, Roberto Pieri, Federica Guerrieri, Ania Naila Serra, Massimo Ibrahim, Toni Mercatali, Laura De Vita, Alessandro |
author_sort | Vanni, Silvia |
collection | PubMed |
description | Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) can be considered as a spectrum of the same disease entity, representing one of the most common adult soft tissue sarcoma (STS) of the extremities. While MFS is rarely metastasizing, it shows an extremely high rate of multiple frequent local recurrences (50–60% of cases). On the other hand, UPS is an aggressive sarcoma prone to distant recurrence, which is correlated to a poor prognosis. Differential diagnosis is challenging due to their heterogeneous morphology, with UPS remaining a diagnosis of exclusion for sarcomas with unknown differentiation lineage. Moreover, both lesions suffer from the unavailability of diagnostic and prognostic biomarkers. In this context, a genomic approach combined with pharmacological profiling could allow the identification of new predictive biomarkers that may be exploited for differential diagnosis, prognosis and targeted therapy, with the aim to improve the management of STS patients. RNA-Seq analysis identified the up-regulation of MMP13 and WNT7B in UPS and the up-regulation of AKR1C2, AKR1C3, BMP7, and SGCG in MFS, which were confirmed by in silico analyses. Moreover, we identified the down-regulation of immunoglobulin genes in patient-derived primary cultures that responded to anthracycline treatment compared to non-responder cultures. Globally, the obtained data corroborated the clinical observation of UPS as an histotype refractory to chemotherapy and the key role of the immune system in determining chemosensitivity of these lesions. Moreover, our results confirmed the validity of genomic approaches for the identification of predictive biomarkers in poorly characterized neoplasms as well as the robustness of our patient-derived primary culture models in recapitulating the chemosensitivity features of STS. Taken as a whole, this body of evidence may pave the way toward an improvement of the prognosis of these rare diseases through a treatment modulation driven by a biomarker-based patient stratification. |
format | Online Article Text |
id | pubmed-10138892 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-101388922023-04-28 Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need Vanni, Silvia Fausti, Valentina Fonzi, Eugenio Liverani, Chiara Miserocchi, Giacomo Spadazzi, Chiara Cocchi, Claudia Calabrese, Chiara Gurrieri, Lorena Riva, Nada Recine, Federica Casadei, Roberto Pieri, Federica Guerrieri, Ania Naila Serra, Massimo Ibrahim, Toni Mercatali, Laura De Vita, Alessandro Int J Mol Sci Article Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) can be considered as a spectrum of the same disease entity, representing one of the most common adult soft tissue sarcoma (STS) of the extremities. While MFS is rarely metastasizing, it shows an extremely high rate of multiple frequent local recurrences (50–60% of cases). On the other hand, UPS is an aggressive sarcoma prone to distant recurrence, which is correlated to a poor prognosis. Differential diagnosis is challenging due to their heterogeneous morphology, with UPS remaining a diagnosis of exclusion for sarcomas with unknown differentiation lineage. Moreover, both lesions suffer from the unavailability of diagnostic and prognostic biomarkers. In this context, a genomic approach combined with pharmacological profiling could allow the identification of new predictive biomarkers that may be exploited for differential diagnosis, prognosis and targeted therapy, with the aim to improve the management of STS patients. RNA-Seq analysis identified the up-regulation of MMP13 and WNT7B in UPS and the up-regulation of AKR1C2, AKR1C3, BMP7, and SGCG in MFS, which were confirmed by in silico analyses. Moreover, we identified the down-regulation of immunoglobulin genes in patient-derived primary cultures that responded to anthracycline treatment compared to non-responder cultures. Globally, the obtained data corroborated the clinical observation of UPS as an histotype refractory to chemotherapy and the key role of the immune system in determining chemosensitivity of these lesions. Moreover, our results confirmed the validity of genomic approaches for the identification of predictive biomarkers in poorly characterized neoplasms as well as the robustness of our patient-derived primary culture models in recapitulating the chemosensitivity features of STS. Taken as a whole, this body of evidence may pave the way toward an improvement of the prognosis of these rare diseases through a treatment modulation driven by a biomarker-based patient stratification. MDPI 2023-04-08 /pmc/articles/PMC10138892/ /pubmed/37108089 http://dx.doi.org/10.3390/ijms24086926 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Vanni, Silvia Fausti, Valentina Fonzi, Eugenio Liverani, Chiara Miserocchi, Giacomo Spadazzi, Chiara Cocchi, Claudia Calabrese, Chiara Gurrieri, Lorena Riva, Nada Recine, Federica Casadei, Roberto Pieri, Federica Guerrieri, Ania Naila Serra, Massimo Ibrahim, Toni Mercatali, Laura De Vita, Alessandro Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need |
title | Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need |
title_full | Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need |
title_fullStr | Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need |
title_full_unstemmed | Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need |
title_short | Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need |
title_sort | unveiling the genomic basis of chemosensitivity in sarcomas of the extremities: an integrated approach for an unmet clinical need |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138892/ https://www.ncbi.nlm.nih.gov/pubmed/37108089 http://dx.doi.org/10.3390/ijms24086926 |
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