Asunto(s)
Biomarcadores de Tumor , Neoplasias Óseas/etiología , Ribonucleósido Difosfato Reductasa/genética , Sarcoma de Ewing/etiología , Animales , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/terapia , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Terapia Molecular Dirigida , Pronóstico , Piridinas/farmacología , Ribonucleósido Difosfato Reductasa/metabolismo , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/terapia , Tiosemicarbazonas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ewing sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1::FLI1 transcription factor drives EwS by orchestrating an oncogenic transcription program through de novo enhancers. By integrative analysis of thousands of transcriptomes representing pan-cancer cell lines, primary cancers, metastasis, and normal tissues, we identify a 32-gene signature (ESS32 [Ewing Sarcoma Specific 32]) that stratifies EwS from pan-cancer. Among the ESS32, LOXHD1, encoding a stereociliary protein, is the most highly expressed gene through an alternative transcription start site. Deletion or silencing of EWSR1::FLI1 bound upstream de novo enhancer results in loss of the LOXHD1 short isoform, altering EWSR1::FLI1 and HIF1α pathway genes and resulting in decreased proliferation/invasion of EwS cells. These observations implicate LOXHD1 as a biomarker and a determinant of EwS metastasis and suggest new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease.