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SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications

Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated in oth...

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Autores principales: Menendez, Sofia T., Rey, Veronica, Martinez-Cruzado, Lucia, Gonzalez, M. Victoria, Morales-Molina, Alvaro, Santos, Laura, Blanco, Verónica, Alvarez, Carlos, Estupiñan, Oscar, Allonca, Eva, Rodrigo, Juan Pablo, García-Castro, Javier, Garcia-Pedrero, Juana Maria, Rodriguez, Rene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226033/
https://www.ncbi.nlm.nih.gov/pubmed/32295077
http://dx.doi.org/10.3390/cancers12040964
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author Menendez, Sofia T.
Rey, Veronica
Martinez-Cruzado, Lucia
Gonzalez, M. Victoria
Morales-Molina, Alvaro
Santos, Laura
Blanco, Verónica
Alvarez, Carlos
Estupiñan, Oscar
Allonca, Eva
Rodrigo, Juan Pablo
García-Castro, Javier
Garcia-Pedrero, Juana Maria
Rodriguez, Rene
author_facet Menendez, Sofia T.
Rey, Veronica
Martinez-Cruzado, Lucia
Gonzalez, M. Victoria
Morales-Molina, Alvaro
Santos, Laura
Blanco, Verónica
Alvarez, Carlos
Estupiñan, Oscar
Allonca, Eva
Rodrigo, Juan Pablo
García-Castro, Javier
Garcia-Pedrero, Juana Maria
Rodriguez, Rene
author_sort Menendez, Sofia T.
collection PubMed
description Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated in other sarcoma subtypes. Here, we show that SOX2 depletion dramatically reduced the ability of undifferentiated pleomorphic sarcoma (UPS) cells to form tumorspheres and to initiate tumor growth. Conversely, SOX2 overexpression resulted in increased in vivo tumorigenicity. Moreover, using a reporter system (SORE6) which allows to monitor viable cells expressing SOX2 and/or OCT4, we found that SORE6+ cells were significantly more tumorigenic than the SORE6- subpopulation. In agreement with this findings, SOX2 expression in sarcoma patients was associated to tumor grade, differentiation, invasive potential and lower patient survival. Finally, we studied the effect of a panel of anti-tumor drugs on the SORE6+ cells of the UPS model and patient-derived chondrosarcoma lines. We found that the mithramycin analogue EC-8042 was the most efficient in reducing SORE6+ cells in vitro and in vivo. Overall, this study demonstrates that SOX2 is a pro-tumorigenic factor with prognostic potential in sarcoma. Moreover, SORE6 transcriptional activity is a bona fide CSC marker in sarcoma and constitutes an excellent biomarker for evaluating the efficacy of anti-tumor treatments on CSC subpopulations.
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spelling pubmed-72260332020-05-18 SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications Menendez, Sofia T. Rey, Veronica Martinez-Cruzado, Lucia Gonzalez, M. Victoria Morales-Molina, Alvaro Santos, Laura Blanco, Verónica Alvarez, Carlos Estupiñan, Oscar Allonca, Eva Rodrigo, Juan Pablo García-Castro, Javier Garcia-Pedrero, Juana Maria Rodriguez, Rene Cancers (Basel) Article Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated in other sarcoma subtypes. Here, we show that SOX2 depletion dramatically reduced the ability of undifferentiated pleomorphic sarcoma (UPS) cells to form tumorspheres and to initiate tumor growth. Conversely, SOX2 overexpression resulted in increased in vivo tumorigenicity. Moreover, using a reporter system (SORE6) which allows to monitor viable cells expressing SOX2 and/or OCT4, we found that SORE6+ cells were significantly more tumorigenic than the SORE6- subpopulation. In agreement with this findings, SOX2 expression in sarcoma patients was associated to tumor grade, differentiation, invasive potential and lower patient survival. Finally, we studied the effect of a panel of anti-tumor drugs on the SORE6+ cells of the UPS model and patient-derived chondrosarcoma lines. We found that the mithramycin analogue EC-8042 was the most efficient in reducing SORE6+ cells in vitro and in vivo. Overall, this study demonstrates that SOX2 is a pro-tumorigenic factor with prognostic potential in sarcoma. Moreover, SORE6 transcriptional activity is a bona fide CSC marker in sarcoma and constitutes an excellent biomarker for evaluating the efficacy of anti-tumor treatments on CSC subpopulations. MDPI 2020-04-13 /pmc/articles/PMC7226033/ /pubmed/32295077 http://dx.doi.org/10.3390/cancers12040964 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Menendez, Sofia T.
Rey, Veronica
Martinez-Cruzado, Lucia
Gonzalez, M. Victoria
Morales-Molina, Alvaro
Santos, Laura
Blanco, Verónica
Alvarez, Carlos
Estupiñan, Oscar
Allonca, Eva
Rodrigo, Juan Pablo
García-Castro, Javier
Garcia-Pedrero, Juana Maria
Rodriguez, Rene
SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications
title SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications
title_full SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications
title_fullStr SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications
title_full_unstemmed SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications
title_short SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications
title_sort sox2 expression and transcriptional activity identifies a subpopulation of cancer stem cells in sarcoma with prognostic implications
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226033/
https://www.ncbi.nlm.nih.gov/pubmed/32295077
http://dx.doi.org/10.3390/cancers12040964
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