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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/8/6926 |
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| author | Silvia Vanni Valentina Fausti Eugenio Fonzi Chiara Liverani Giacomo Miserocchi Chiara Spadazzi Claudia Cocchi Chiara Calabrese Lorena Gurrieri Nada Riva Federica Recine Roberto Casadei Federica Pieri Ania Naila Guerrieri Massimo Serra Toni Ibrahim Laura Mercatali Alessandro De Vita |
| author_facet | Silvia Vanni Valentina Fausti Eugenio Fonzi Chiara Liverani Giacomo Miserocchi Chiara Spadazzi Claudia Cocchi Chiara Calabrese Lorena Gurrieri Nada Riva Federica Recine Roberto Casadei Federica Pieri Ania Naila Guerrieri Massimo Serra Toni Ibrahim Laura Mercatali Alessandro De Vita |
| author_sort | Silvia Vanni |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T04:56:50Z |
| format | Article |
| id | doaj.art-22f3955d551c41c5ae43cac4fdcf5d62 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:56:50Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-22f3955d551c41c5ae43cac4fdcf5d622023-11-17T19:32:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01248692610.3390/ijms24086926Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical NeedSilvia Vanni0Valentina Fausti1Eugenio Fonzi2Chiara Liverani3Giacomo Miserocchi4Chiara Spadazzi5Claudia Cocchi6Chiara Calabrese7Lorena Gurrieri8Nada Riva9Federica Recine10Roberto Casadei11Federica Pieri12Ania Naila Guerrieri13Massimo Serra14Toni Ibrahim15Laura Mercatali16Alessandro De Vita17Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyClinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyBiostatistics and Clinical Trials Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyPreclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyPreclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyPreclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyPreclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyPreclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyClinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyClinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyMedical Oncology Unit, Azienda Ospedaliera “San Giovanni Addolorata”, 00184 Roma, ItalyGeneral and Oncologic Surgery, “Morgagni-Pierantoni” Hospital, 47121 Forlì, ItalyPathology Unit, “Morgagni-Pierantoni” Hospital, 47121 Forlì, ItalyOsteoncologia, Sarcomi dell’osso e dei tessuti molli, e Terapie Innovative, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, ItalyOsteoncologia, Sarcomi dell’osso e dei tessuti molli, e Terapie Innovative, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, ItalyOsteoncologia, Sarcomi dell’osso e dei tessuti molli, e Terapie Innovative, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, ItalyPreclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyPreclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, ItalyMyxofibrosarcoma (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.https://www.mdpi.com/1422-0067/24/8/6926myxofibrosarcomaundifferentiated pleomorphic sarcomagenomicschemosensitivitypatient-derived cultures |
| spellingShingle | Silvia Vanni Valentina Fausti Eugenio Fonzi Chiara Liverani Giacomo Miserocchi Chiara Spadazzi Claudia Cocchi Chiara Calabrese Lorena Gurrieri Nada Riva Federica Recine Roberto Casadei Federica Pieri Ania Naila Guerrieri Massimo Serra Toni Ibrahim Laura Mercatali Alessandro De Vita Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need International Journal of Molecular Sciences myxofibrosarcoma undifferentiated pleomorphic sarcoma genomics chemosensitivity patient-derived cultures |
| 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 | myxofibrosarcoma undifferentiated pleomorphic sarcoma genomics chemosensitivity patient-derived cultures |
| url | https://www.mdpi.com/1422-0067/24/8/6926 |
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