TY - JOUR
T1 - HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS) :
T2 - A Spanish Group for Research on Sarcomas (GEIS) study
AU - Moura, David S.
AU - Mondaza-Hernandez, Jose L.
AU - Sanchez-Bustos, Paloma
AU - Peña-Chilet, Maria
AU - Cordero-Varela, Juan A.
AU - Lopez-Alvarez, Maria
AU - Carrillo-Garcia, Jaime
AU - Martin-Ruiz, Marta
AU - Romero-Gonzalez, Pablo
AU - Renshaw-Calderon, Marta
AU - Ramos, Rafael
AU - Marcilla, David
AU - Alvarez-Alegret, Ramiro
AU - Agra Pujol, Carolina
AU - Izquierdo, Francisco
AU - Ortega-Medina, Luis
AU - Martin-Davila, Francisco
AU - Hernandez-Leon, Carmen Nieves
AU - Romagosa, Cleofe
AU - Salgado, Maria Angeles Vaz
AU - Lavernia, Javier
AU - Bagué Rosell, Sílvia
AU - Mayodormo-Aranda, Empar
AU - Alvarez, Rosa
AU - Valverde, Claudia
AU - Martinez-Trufero, Javier
AU - Castilla-Ramirez, Carolina
AU - Gutierrez, Antonio
AU - Dopazo, Joaquín
AU - Hindi, Nadia
AU - Garcia-Foncillas, Jesus
AU - Martin-Broto, Javier
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/5/17
Y1 - 2024/5/17
N2 - 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.
AB - 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.
KW - HMGA1
KW - Leiomyosarcoma
KW - Soft-tissue sarcoma
KW - Trabectedin
KW - mTOR pathway
KW - Prognosis
KW - Humans
KW - Sarcoma/drug therapy
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Signal Transduction/drug effects
KW - Leiomyosarcoma/drug therapy
KW - Xenograft Model Antitumor Assays
KW - Animals
KW - Antineoplastic Agents, Alkylating/pharmacology
KW - HMGA1a Protein/metabolism
KW - Drug Resistance, Neoplasm/genetics
KW - Cell Line, Tumor
KW - Female
KW - Mice
KW - TOR Serine-Threonine Kinases/metabolism
KW - Trabectedin/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85193549482&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/a3740c73-3f32-391e-872c-970607de4a37/
U2 - 10.1007/s00018-024-05250-y
DO - 10.1007/s00018-024-05250-y
M3 - Article
C2 - 38758230
SN - 1420-9071
VL - 81
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 1
M1 - 219
ER -