HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS)
HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:292716 |
| Acceso en línea: | https://ddd.uab.cat/record/292716 https://dx.doi.org/urn:doi:10.1007/s00018-024-05250-y |
| Access Level: | acceso abierto |
| Palabra clave: | HMGA1 Leiomyosarcoma Mtor pathway Soft-tissue sarcoma Trabectedin |
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HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS)A Spanish Group for Research on Sarcomas (GEIS) studyMoura, David S.Mondaza-Hernandez, Jose L.Sanchez-Bustos, PalomaPeña-Chilet, MariaCordero-Varela, Juan A.Lopez-Alvarez, MariaCarrillo-Garcia, JaimeMartin-Ruiz, MartaRomero-Gonzalez, PabloRenshaw-Calderon, MartaRamos, Rafel|||0000-0001-7970-5537Marcilla, DavidAlvarez-Alegret, RamiroAgra Pujol, Carolina|||0000-0003-4843-5786Izquierdo, FranciscoOrtega-Medina, LuisMartin-Davila, FranciscoHernandez-Leon, Carmen NievesRomagosa Perez Portabella, Maria Cleofe|||0000-0002-9478-7320Salgado, Maria Angeles VazLavernia, JavierBagué Rosell, Sílvia|||0000-0001-9980-7231Mayodormo-Aranda, EmparAlvarez, Rosa|||0000-0003-0935-8298Valverde Morales, Claudia MariaMartínez Trufero, Javier|||0000-0002-0997-2573Castilla-Ramirez, CarolinaGutiérrez, Antonio|||0000-0001-9062-077XDopazo, Joaquín|||0000-0003-3318-120XHindi, Nadia|||0000-0002-5864-762XGarcia-Foncillas, JesusMartín-Broto, Javier|||0000-0001-7350-6916HMGA1LeiomyosarcomaMtor pathwaySoft-tissue sarcomaTrabectedinHMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.Universitat Autònoma de Barcelona. Departament de Ciències Morfològiques 22024-01-0120242024-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/292716https://dx.doi.org/urn:doi:10.1007/s00018-024-05250-yreponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengEuropean Commission https://doi.org/10.13039/501100000780 825806open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2927162026-06-06T12:50:31Z |
| dc.title.none.fl_str_mv |
HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS) A Spanish Group for Research on Sarcomas (GEIS) study |
| title |
HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS) |
| spellingShingle |
HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS) Moura, David S. HMGA1 Leiomyosarcoma Mtor pathway Soft-tissue sarcoma Trabectedin |
| title_short |
HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS) |
| title_full |
HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS) |
| title_fullStr |
HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS) |
| title_full_unstemmed |
HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS) |
| title_sort |
HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS) |
| dc.creator.none.fl_str_mv |
Moura, David S. Mondaza-Hernandez, Jose L. Sanchez-Bustos, Paloma Peña-Chilet, Maria Cordero-Varela, Juan A. Lopez-Alvarez, Maria Carrillo-Garcia, Jaime Martin-Ruiz, Marta Romero-Gonzalez, Pablo Renshaw-Calderon, Marta Ramos, Rafel|||0000-0001-7970-5537 Marcilla, David Alvarez-Alegret, Ramiro Agra Pujol, Carolina|||0000-0003-4843-5786 Izquierdo, Francisco Ortega-Medina, Luis Martin-Davila, Francisco Hernandez-Leon, Carmen Nieves Romagosa Perez Portabella, Maria Cleofe|||0000-0002-9478-7320 Salgado, Maria Angeles Vaz Lavernia, Javier Bagué Rosell, Sílvia|||0000-0001-9980-7231 Mayodormo-Aranda, Empar Alvarez, Rosa|||0000-0003-0935-8298 Valverde Morales, Claudia Maria Martínez Trufero, Javier|||0000-0002-0997-2573 Castilla-Ramirez, Carolina Gutiérrez, Antonio|||0000-0001-9062-077X Dopazo, Joaquín|||0000-0003-3318-120X Hindi, Nadia|||0000-0002-5864-762X Garcia-Foncillas, Jesus Martín-Broto, Javier|||0000-0001-7350-6916 |
| author |
Moura, David S. |
| author_facet |
Moura, David S. Mondaza-Hernandez, Jose L. Sanchez-Bustos, Paloma Peña-Chilet, Maria Cordero-Varela, Juan A. Lopez-Alvarez, Maria Carrillo-Garcia, Jaime Martin-Ruiz, Marta Romero-Gonzalez, Pablo Renshaw-Calderon, Marta Ramos, Rafel|||0000-0001-7970-5537 Marcilla, David Alvarez-Alegret, Ramiro Agra Pujol, Carolina|||0000-0003-4843-5786 Izquierdo, Francisco Ortega-Medina, Luis Martin-Davila, Francisco Hernandez-Leon, Carmen Nieves Romagosa Perez Portabella, Maria Cleofe|||0000-0002-9478-7320 Salgado, Maria Angeles Vaz Lavernia, Javier Bagué Rosell, Sílvia|||0000-0001-9980-7231 Mayodormo-Aranda, Empar Alvarez, Rosa|||0000-0003-0935-8298 Valverde Morales, Claudia Maria Martínez Trufero, Javier|||0000-0002-0997-2573 Castilla-Ramirez, Carolina Gutiérrez, Antonio|||0000-0001-9062-077X Dopazo, Joaquín|||0000-0003-3318-120X Hindi, Nadia|||0000-0002-5864-762X Garcia-Foncillas, Jesus Martín-Broto, Javier|||0000-0001-7350-6916 |
| author_role |
author |
| author2 |
Mondaza-Hernandez, Jose L. Sanchez-Bustos, Paloma Peña-Chilet, Maria Cordero-Varela, Juan A. Lopez-Alvarez, Maria Carrillo-Garcia, Jaime Martin-Ruiz, Marta Romero-Gonzalez, Pablo Renshaw-Calderon, Marta Ramos, Rafel|||0000-0001-7970-5537 Marcilla, David Alvarez-Alegret, Ramiro Agra Pujol, Carolina|||0000-0003-4843-5786 Izquierdo, Francisco Ortega-Medina, Luis Martin-Davila, Francisco Hernandez-Leon, Carmen Nieves Romagosa Perez Portabella, Maria Cleofe|||0000-0002-9478-7320 Salgado, Maria Angeles Vaz Lavernia, Javier Bagué Rosell, Sílvia|||0000-0001-9980-7231 Mayodormo-Aranda, Empar Alvarez, Rosa|||0000-0003-0935-8298 Valverde Morales, Claudia Maria Martínez Trufero, Javier|||0000-0002-0997-2573 Castilla-Ramirez, Carolina Gutiérrez, Antonio|||0000-0001-9062-077X Dopazo, Joaquín|||0000-0003-3318-120X Hindi, Nadia|||0000-0002-5864-762X Garcia-Foncillas, Jesus Martín-Broto, Javier|||0000-0001-7350-6916 |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universitat Autònoma de Barcelona. Departament de Ciències Morfològiques |
| dc.subject.none.fl_str_mv |
HMGA1 Leiomyosarcoma Mtor pathway Soft-tissue sarcoma Trabectedin |
| topic |
HMGA1 Leiomyosarcoma Mtor pathway Soft-tissue sarcoma Trabectedin |
| description |
HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2 2024-01-01 2024 2024-01-01 |
| dc.type.none.fl_str_mv |
Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://ddd.uab.cat/record/292716 https://dx.doi.org/urn:doi:10.1007/s00018-024-05250-y |
| url |
https://ddd.uab.cat/record/292716 https://dx.doi.org/urn:doi:10.1007/s00018-024-05250-y |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
European Commission https://doi.org/10.13039/501100000780 825806 |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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reponame:Dipòsit Digital de Documents de la UAB instname:Universitat Autònoma de Barcelona |
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Universitat Autònoma de Barcelona |
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Dipòsit Digital de Documents de la UAB |
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Dipòsit Digital de Documents de la UAB |
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