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

Abstract

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.

Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents

“…In a reporter system (SORE6), which allows the monitoring of viable cells expressing Sox2 and/or Oct4, SORE6 + cells were found to be significantly more tumorigenic than SORE6cells. 60,73 Side population (SP) cells SP cells were discovered in 1996 by M A Goodell in hematopoietic stem cells (HSCs): SP cells were not stained by Hoechst 33342. 74 SP fractions were shown to protect recipients from lethal irradiation at low cell doses, and to contribute to both lymphoid and myeloid lineages.…”

Biological Heterogeneity of Chondrosarcoma: From (Epi) Genetics through Stemness and Deregulated Signaling to Immunophenotype

“…Significant evidence shows that aldehyde dehydrogenase (ALDH) or CD133 can be considered potentially useful therapeutic targets for eliminating CSCs [ 43 ]. Many data suggest the potential prognostic relevance of SSC/CSC marker abnormalities in clinical practice [ 39 , 40 , 44 ].…”

“…At the same time, its upregulation significantly enhanced pro-tumorigenic activity in vivo. Among sarcomas, the role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma [ 44 ]. Moreover, a correlation of SOX2 expression with tumor grade, invasiveness, and patients’ lower survival was found [ 44 ].…”

“…Among sarcomas, the role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma [ 44 ]. Moreover, a correlation of SOX2 expression with tumor grade, invasiveness, and patients’ lower survival was found [ 44 ]. SOX9, another well-established pluripotency transcription factor playing an essential role in chondrogenesis, was found to be overexpressed in conventional, mesenchymal, and clear cell ChSs, and downregulation was observed in dedifferentiated ChS [ 47 , 48 ].…”

Tumor-targeted delivery of siRNA to silence Sox2 gene expression enhances therapeutic response in hepatocellular carcinoma

“…Sox2 as a critical transcriptional regulator is overexpressed in the majority of solid cancers, such as HCC, lung cancer, colorectal and breast cancer [ 22 ]. Overexpression of Sox2 promotes the proliferation, migration, invasion and tumorigenicity of cancer cells [ 23 ].…”