Sistema de Salut de Catalunya
Mondaza Hernandez, Jose Lucinio
Romagosa Pérez-Portabell, Cleofé
Institut Català de la Salut
[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
Vall d'Hebron Barcelona Hospital Campus
2024-05-23T10:09:19Z
2024-05-23T10:09:19Z
2024-05-17
Leiomyosarcoma; Soft-tissue sarcoma; Trabectedin
Leiomiosarcoma; Sarcoma de teixit tou; Trabectedina
Leiomiosarcoma; Sarcoma de tejido blando; Trabectedina
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.
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).
Article
Published version
English
Tumors de parts toves - Tractament; Medicaments antineoplàstics - Ús terapèutic; Resistència als medicaments; DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Connective and Soft Tissue::Neoplasms, Muscle Tissue::Leiomyosarcoma; Other subheadings::Other subheadings::Other subheadings::/drug therapy; PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm; CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents; Other subheadings::Other subheadings::/therapeutic use; ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de tejido conjuntivo y de tejidos blandos::neoplasias de tejido muscular::leiomiosarcoma; Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia; FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos; COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos; Otros calificadores::Otros calificadores::/uso terapéutico
Springer
Cellular and Molecular Life Sciences;81(1)
https://doi.org/10.1007/s00018-024-05250-y
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
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