dc.contributor
Institut Català de la Salut
dc.contributor
[Moura DS] Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IISFJD, UAM), Madrid, Spain. Department of Oncology in University Hospital Fundación Jiménez Díaz, Madrid, Spain. [Mondaza-Hernandez JL] Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IISFJD, UAM), Madrid, Spain. [Sanchez-Bustos P, Cordero-Varela JA, Lopez-Alvarez M] Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla), Seville, Spain. [Peña-Chilet M] Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla), Seville, Spain. Clinical Bioinformatics Area, Fundación Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocio, Seville, Spain. Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, Seville, Spain. [Romagosa C] Servei d’Anatomia Patològica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Valverde C] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain
dc.contributor
Vall d'Hebron Barcelona Hospital Campus
dc.contributor.author
Mondaza Hernandez, Jose Lucinio
dc.contributor.author
Sanchez-Bustos, Paloma
dc.contributor.author
López Álvarez, María
dc.contributor.author
Romagosa Pérez-Portabell, Cleofé
dc.contributor.author
Valverde Morales, Claudia Maria
dc.contributor.author
Moura, David
dc.contributor.author
Peña-Chilet, Maria
dc.contributor.author
Cordero Varela, Juan Antonio
dc.date.accessioned
2025-10-24T10:35:18Z
dc.date.available
2025-10-24T10:35:18Z
dc.date.issued
2024-05-23T10:09:19Z
dc.date.issued
2024-05-23T10:09:19Z
dc.date.issued
2024-05-17
dc.identifier
Moura DS, Mondaza-Hernandez JL, Sanchez-Bustos P, Peña-Chilet M, Cordero-Varela JA, Lopez-Alvarez M, et al. HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study. Cell Mol Life Sci. 2024 May 17;81(1):219.
dc.identifier
https://hdl.handle.net/11351/11493
dc.identifier
10.1007/s00018-024-05250-y
dc.identifier.uri
https://hdl.handle.net/11351/11493
dc.description.abstract
Leiomyosarcoma; Soft-tissue sarcoma; Trabectedin
dc.description.abstract
Leiomiosarcoma; Sarcoma de teixit tou; Trabectedina
dc.description.abstract
Leiomiosarcoma; Sarcoma de tejido blando; Trabectedina
dc.description.abstract
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.
dc.description.abstract
This study was partially funded by the Spanish group for research on sarcoma (GEIS; Grant number: GEIS-38) and by PharmaMar (institutional research grant; Grant number: NA).
dc.format
application/pdf
dc.relation
Cellular and Molecular Life Sciences;81(1)
dc.relation
https://doi.org/10.1007/s00018-024-05250-y
dc.rights
Attribution 4.0 International
dc.rights
http://creativecommons.org/licenses/by/4.0/
dc.rights
info:eu-repo/semantics/openAccess
dc.subject
Tumors de parts toves - Tractament
dc.subject
Medicaments antineoplàstics - Ús terapèutic
dc.subject
Resistència als medicaments
dc.subject
DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Connective and Soft Tissue::Neoplasms, Muscle Tissue::Leiomyosarcoma
dc.subject
Other subheadings::Other subheadings::Other subheadings::/drug therapy
dc.subject
PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm
dc.subject
CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents
dc.subject
Other subheadings::Other subheadings::/therapeutic use
dc.subject
ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de tejido conjuntivo y de tejidos blandos::neoplasias de tejido muscular::leiomiosarcoma
dc.subject
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
dc.subject
FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos
dc.subject
COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos
dc.subject
Otros calificadores::Otros calificadores::/uso terapéutico
dc.title
HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study
dc.type
info:eu-repo/semantics/article
dc.type
info:eu-repo/semantics/publishedVersion
