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.
Highlights
Similar to normal tissues, the cancer stem cell model proposes that tumors are hierarchically organized and at the apex of this structure there are cells presenting stem cell like properties able to self-renew and to differentiate and give rise to the rest of subpopulations present in the tumor [1]
By comparing the tumorigenic properties of these models with those of their xenograft-derived cell lines, we found that SOX2 expression was progressively enhanced in cancer stem cells (CSC)-enriched tumorspheres during sarcoma progression toward more aggressive phenotypes, highlighting its potential applicability as CSC marker in sarcomas [35]
To further and significantly extend these data, we introduced a reporter system to monitor the transcriptional activity due to SOX2 and/or OCT4 (SORE6) [29] in a model of undifferentiated pleomorphic sarcoma (UPS) and chondrosarcoma patient-derived cell lines analyzing for the first time the ability of isolated SOX2/OCT4-positive cells as tumor-promoting
Summary
The cancer stem cell model proposes that tumors are hierarchically organized and at the apex of this structure there are cells presenting stem cell like properties (cancer stem cells, CSCs) able to self-renew and to differentiate and give rise to the rest of subpopulations present in the tumor [1]. Cancers 2020, 12, 964 re-initiate tumor growth They have enhanced ability to migrate and invade tissues and show increased resistance to chemotherapeutic drugs. A common characteristic of CSC subpopulations is the overexpression of transcription factors responsible for maintenance of the stem cell phenotype in embryonic and adult stem cells like SOX2 (Sex-determining region Y-box protein 2) or OCT4. (POU5F1, POU Class 5 Homeobox 1) [2] Subpopulations expressing these pluripotency factors have been correlated with tumor progression, drug resistance and the presence of hierarchically organized CSCs in several types of tumors [3,4,5,6,7,8]. OCT-4 expression was associated to CSCs subpopulations in
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