Sox2 Functions in Neural Cancer Stem Cells: The Importance of the Context

Abstract

The Sox2 transcription factor is expressed in different neural tumors. In particular, it is active within the "cancer stem cell" (CSC) subpopulation of tumor cells, able to reinitiate tumorigenesis after conventional chemotherapy (to which it is usually resistant). This led to hypothesize that Sox2 (and its downstream regulated genes) may qualify as promising targets for therapeutic strategies directed against CSC. However, the potential relevance of Sox2 in this regard depends on whether it is functionally important to maintain CSC. Here, we comparatively examine the effects of Sox2 genetic ablation within mouse models of different neural tumor types. Sox2 ablation in mouse glioma (and in human glioblastomaderived CSC) demonstrated a critical function for Sox2 in the maintenance of CSC. Surprisingly, however, Sox2 ablation in two different mouse models of melanoma (a neural crest-related tumor), and in a mouse model of medulloblastoma of the Sonic Hedgehog subgroup, showed that, in these contexts, Sox2 is dispensable for tumorigenesis. This heterogeneous situation has a parallel in the normal development of the nervous system, where generalized Sox2 ablation in neural stem/ progenitor cells selectively affects the development of some neural regions, but not other ones. Molecular mechanisms underlying these specificities may involve the regulation, by Sox2, of different sets of target genes in different tumors, but also a redundant regulation of the same targets by different Sox transcription factors, differentially coexpressed with Sox2 in different tumors. Collectively, these findings point to the need to experimentally address the requirement for Sox2, and its downstream targets, within different tumor types, as a prerequisite to fully exploit its potential as a target for novel therapeutic approaches.

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

“…Sox2 is overexpressed in a variety of tumors (Barone et al, 2018;Cesarini et al, 2017;Schaefer et al, 2017), by unknown mechanisms, possibly via dysregulation of miR:Sox2 axes (Sathyan et al, 2015).…”

“…The ability of Sox2 to maintain ES and NSC led to the hypothesis that Sox2 may retain, in CSC, and specifically in GSC, an essential role (Barone et al, 2018;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 et al, 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), that is, its ability to sustain tumorigenesis, to a broad sample of tumor types.…”