Los genes EMX (Empty Spiracles Homeobox), EMX1 y EMX2, son dos miembros de la familia de factores de transcripción implicados en la proliferación y diferenciación de las células madre neurales. En sarcomas, EMX1 y EMX2 actúan como supresores de tumores al reprimir la actividad de genes reguladores de células madre. La represión de EMX indujo la malignidad y stemness de las células tanto in vitro como in vivo. En modelos de knockout murinos que carecen de estos genes, los sarcomas eran más agresivos e infiltrantes y tenían una mayor capacidad de autorrenovación tumoral. Estos resultados muestran que los genes EMX actuaban como reguladores de stemness en diferentes subtipos de sarcoma, sugiriendo un efecto común. En este trabajo, mostramos que la vía canónica de Wnt es uno de los mecanismos que explica las relaciones de EMX1/EMX2 y los genes de células madre en el sarcoma. La relación Wnt-EMX1/EMX2 se validó in silico con conjuntos de datos de pacientes con sarcoma, in vitro en líneas celulares de sarcoma derivadas primarias e in vivo. Se encontró que la expresión de EMX regula negativamente la ruta de Wnt. Además, la activación constitutiva de la vía Wnt revierte a un fenotipo más agresivo con propiedades de células madre, y la transcripción de los genes de stemness aumentó incluso en presencia de sobreexpresión de EMX1 y/o EMX2, estableciendo la relación entre la vía Wnt, los genes de células madre y los factores de transcripción EMX.
Resumen
Background:
Sarcomas are a very heterogeneous group of tumors with intrinsic developmental programs derived from the cell of origin. This implies a functional hierarchy inside tumors governed by sarcoma stem cells. Therefore, genetic and/or epigenetic changes profoundly affect the biology of sarcoma tumor stem cells. EMX genes are proposed to be transcription factors that are involved in the sarcomagenesis process, regardless of the neural or mesodermal embryological sarcoma origin. It has been shown that EMX1 or EMX2 overexpression reduces tumorigenic properties, while reducing the levels of these genes enhances these properties. Furthermore, it has been shown that EMX genes decrease the expression of stem cell regulatory genes and the stem cell phenotype. Taken together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-remodeling populations or sarcoma stem cells, acting as tumor suppressors in sarcoma.
Methods:
Bioinformatic analysis, quantitative mRNA and protein expression analysis, cell models of sarcoma by ectopic expression of EMX genes. By cell biology methods we measured tumorigenesis and populations enriched on stem cell phenotypes, either in vitro or in vivo.
Results:
In this work, we showed that the canonical Wnt pathway is one of the mechanisms that explains the relationships of EMX1/EMX2 and stem cell genes in sarcoma. The Wnt-EMX1/EMX2 relationship was validated in silico with sarcoma patient datasets, in vitro in primary derived sarcoma cell lines, and in vivo. EMX expression was found to negatively regulate the Wnt pathway. In addition, the constitutive activation of the Wnt pathway revers to a more aggressive phenotype with stem cell properties, and stemness gene transcription increased even in the presence of EMX1 and/or EMX2 overexpression, establishing the relationship among the Wnt pathway, stem cell genes and the EMX transcription factors.
Conclusions:
Our data showed that Empty Spiracles Homeobox Genes EMX1 and EMX2 represses WNT signalling and activation of WNT pathway bypass EMX-dependent stemness repression and induces sarcomagenesis. These results also suggest the relevance of the Wnt/b-catenin/stemness axis as a therapeutic target in sarcoma.
Keywords:
Cancer; Cancer stem cells; EMX; Sarcoma; Wnt pathway; b-catenin.
Sarcomas are a very heterogeneous group of tumors with intrinsic developmental programs derived from the cell of origin. This implies a functional hierarchy inside tumors governed by sarcoma stem cells. Therefore, genetic and/or epigenetic changes profoundly affect the biology of sarcoma tumor stem cells. EMX genes are proposed to be transcription factors that are involved in the sarcomagenesis process, regardless of the neural or mesodermal embryological sarcoma origin. It has been shown that EMX1 or EMX2 overexpression reduces tumorigenic properties, while reducing the levels of these genes enhances these properties. Furthermore, it has been shown that EMX genes decrease the expression of stem cell regulatory genes and the stem cell phenotype. Taken together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-remodeling populations or sarcoma stem cells, acting as tumor suppressors in sarcoma.
Methods:
Bioinformatic analysis, quantitative mRNA and protein expression analysis, cell models of sarcoma by ectopic expression of EMX genes. By cell biology methods we measured tumorigenesis and populations enriched on stem cell phenotypes, either in vitro or in vivo.
Results:
In this work, we showed that the canonical Wnt pathway is one of the mechanisms that explains the relationships of EMX1/EMX2 and stem cell genes in sarcoma. The Wnt-EMX1/EMX2 relationship was validated in silico with sarcoma patient datasets, in vitro in primary derived sarcoma cell lines, and in vivo. EMX expression was found to negatively regulate the Wnt pathway. In addition, the constitutive activation of the Wnt pathway revers to a more aggressive phenotype with stem cell properties, and stemness gene transcription increased even in the presence of EMX1 and/or EMX2 overexpression, establishing the relationship among the Wnt pathway, stem cell genes and the EMX transcription factors.
Conclusions:
Our data showed that Empty Spiracles Homeobox Genes EMX1 and EMX2 represses WNT signalling and activation of WNT pathway bypass EMX-dependent stemness repression and induces sarcomagenesis. These results also suggest the relevance of the Wnt/b-catenin/stemness axis as a therapeutic target in sarcoma.
Keywords:
Cancer; Cancer stem cells; EMX; Sarcoma; Wnt pathway; b-catenin.
enero 2023
Referencia del artículo
https://pubmed.ncbi.nlm.nih.gov/34364391/
Sobre el grupo investigador
El grupo de “Biología molecular del cáncer”, dirigido por Amancio Carnero, investigador del CSIC en el Instituto de Biomedicina de Sevilla en el Departamento de Oncohematología y Genética. Se encuentra vinculado y ubicado en el campus universitario del Hospital Universitario Virgen del Rocío/US/CSIC. Adicionalmente, el grupo pertenece al CIBER de Cáncer (CIBERONC). Las líneas de investigación principales del grupo se han centrado en 2 vías paralelas. Por un lado la medicina de precisión, con especial hincapié en biomarcadores predictivos de eficacia y biomarcadores pronóstico en distintos modelos tumorales. Por otro lado, se basa en el desarrollo de la búsqueda y caracterización de nuevas alteraciones genéticas y epigenéticas que tengan relevancia en cáncer.
Finalmente, el Instituto de Biomedicina de Sevilla (IBiS) es un centro multidisciplinar cuyo objetivo es llevar a cabo investigación fundamental sobre las causas y mecanismos de las patologías más prevalentes en la población y el desarrollo de nuevos métodos de diagnóstico y tratamiento para las mismas.