HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS) : A Spanish Group for Research on Sarcomas (GEIS) study
Moura, David S. (Hospital Universitario Fundación Jiménez Díaz)
Mondaza-Hernandez, Jose L. (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Sanchez-Bustos, Paloma (Universidad de Sevilla)
Peña-Chilet, Maria (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Cordero-Varela, Juan A. (Universidad de Sevilla)
Lopez-Alvarez, Maria (Universidad de Sevilla)
Carrillo-Garcia, Jaime (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Martin-Ruiz, Marta (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Romero-Gonzalez, Pablo (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Renshaw-Calderon, Marta (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Ramos, Rafael (Hospital Universitari Son Espases (Palma de Mallorca, Balears))
Marcilla, David (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Alvarez-Alegret, Ramiro (Hospital Universitario Miguel Servet (Saragossa))
Agra Pujol, Carolina (Hospital General Universitario Gregorio Marañón)
Izquierdo, Francisco (Complejo Asistencial Universitario de León)
Ortega-Medina, Luis (Hospital Clínico San Carlos (Madrid))
Martin-Davila, Francisco (Hospital General Universitario de Ciudad Real)
Hernandez-Leon, Carmen Nieves (Hospital Universitario de Canarias (La Laguna))
Romagosa, Cleofe (Hospital Universitari Vall d'Hebron)
Salgado, Maria Angeles Vaz (Hospital Universitario Ramón y Cajal (Madrid))
Lavernia, Javier (Fundació Institut Valencià d'Oncologia)
Bagué Rosell, Sílvia (Institut de Recerca Sant Pau)
Mayodormo-Aranda, Empar (Hospital Universitari i Politècnic La Fe (València))
Alvarez, Rosa (Hospital General Universitario Gregorio Marañón)
Valverde, Claudia (Hospital Universitari Vall d'Hebron)
Martinez-Trufero, Javier (Hospital Universitario Miguel Servet (Saragossa))
Castilla-Ramirez, Carolina (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Gutiérrez, Antonio (Hospital Universitari Son Espases (Palma de Mallorca, Balears))
Dopazo, Joaquín (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Hindi, Nadia (Hospital Universitario General de Villalba)
Garcia-Foncillas, Jesus (Hospital Universitario General de Villalba)
Martin-Broto, Javier (Hospital Universitario Fundación Jiménez Díaz)
Universitat Autònoma de Barcelona. Departament de Ciències Morfològiques

Data:	2024
Resum:	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.
Ajuts:	European Commission. Horizon 2020 825806
Drets:	Aquest 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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	HMGA1 ; Leiomyosarcoma ; Mtor pathway ; Soft-tissue sarcoma ; Trabectedin
Publicat a:	Cellular and molecular life sciences, Vol. 81 Núm. 1 (december 2024) , p. 219, ISSN 1420-9071

DOI: 10.1007/s00018-024-05250-y
PMID: 38758230

18 p, 5.8 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Recerca Sant Pau
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