Sox2 is dispensable for primary melanoma and metastasis formation

Abstract

Tumor initiation and metastasis formation in many cancers have been associated with emergence of a gene expression program normally active in embryonic or organ-specific stem cells. In particular, the stem cell transcription factor Sox2 is not only expressed in a variety of tumors, but is also required for their formation. Melanoma, the most aggressive skin tumor, derives from melanocytes that during development originate from neural crest stem cells. While neural crest stem cells do not express Sox2, expression of this transcription factor has been reported in melanoma. However, the role of Sox2 in melanoma is controversial. To study the requirement of Sox2 for melanoma formation, we therefore performed CRISPR-Cas9-mediated gene inactivation in human melanoma cells. In addition, we conditionally inactivated Sox2 in a genetically engineered mouse model, in which melanoma spontaneously develops in the context of an intact stroma and immune system. Surprisingly, in both models, loss of Sox2 did neither affect melanoma initiation, nor growth, nor metastasis formation. The lack of a tumorigenic role of Sox2 in melanoma might reflect a distinct stem cell program active in neural crest stem cells and during melanoma formation.

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

“…Similarly as previously shown [73], vemurafenib resistance was developed independently from SOX2 expression in drug-naïve cells, however, while in the study of Cesarini et al, SOX2 was strongly upregulated only in one out of three vemurafenib-resistant cell lines, in our study SOX2 upregulation was observed in all six PLXR cell lines. As several reports suggest genetic context-dependent role of SOX2 in melanoma [73][74][75][76][77], regulation of SOX2 expression and the role of this transcription factor in resistant melanoma cells remain to be clarified.…”

Cancer Stem Cell Subpopulations Are Present Within Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma

“…If SOX2 is dispensable following metastasis in mHNcSCC as in metastatic malignant melanoma (58), a correlation between low SOX2 expression levels and a more aggressive cancer may be expected. However, Li et al (59) demonstrate that SOX2 is a downstream target of the Hippo effector TAZ in HNcSCC, which is capable of reprogramming differentiated cancer cells into CSCs, and that SOX2 and TAZ upregulation are both associated with poorer overall survival in HNcSCC.…”

Sox2-dependent maintenance of mouse oligodendroglioma involves the Sox2-mediated downregulation of Cdkn2b, Ebf1, Zfp423 and Hey2

“…Sox2 is also overexpressed in a variety of tumors (Barone, 2018;Cesarini et al, 2017;Schaefer et al, 2017). The discovery of cancer stem cells (CSC), a subset of tumor cells able to behave as "tumor-reinitiating cells", capable to reform the tumor of origin following conventional chemotherapy (to which CSC are usually resistant) (Nicolis, 2007;Singh et al, 2004), led to the hypothesis that Sox2 may retain, in these pathological stem cells, an essential role (Barone, 2018;Nicolis, 2007;Wuebben & Rizzino, 2017).…”

“…Additionally, the importance of SOX2 in tumorigenesis and CSC was widened to various different tumor types: for example, SOX2 amplification was identified as an oncogenic driver of esophageal and lung squamous cell carcinoma, a common type of lung cancer (Bass et al, 2009), and SOX2 was found to be required within skin tumors stem cells (Boumahdi et al, 2014). An exception to these findings is represented by the Sox2-expressing neural crest-derived tumor melanoma; indeed, Sox2 conditional deletion in two different mouse models showed that Sox2 is entirely dispensable for tumorigenesis in both cases (Barone, 2018;Cesarini et al, 2017;Schaefer et al, 2017). Overall, these findings extend the significance of the study of the "dark side of Sox2" (Wuebben & Rizzino, 2017), i.e.…”