Sox9 Controls Self-Renewal of Oncogene Targeted Cells and Links Tumor Initiation and Invasion

Sox9 is a transcription factor expressed in most solid tumors. However, the molecular mechanisms underlying Sox9 function during tumorigenesis remain unclear. Here, using a genetic mouse model of basal cell carcinoma (BCC), the most frequent cancer in humans, we show that Sox9 is expressed from the earliest step of tumor formation in a Wnt/β-catenin-dependent manner. Deletion of Sox9 together with the constitutive activation of Hedgehog signaling completely prevents BCC formation and leads to a progressive loss of oncogene-expressing cells. Transcriptional profiling of oncogene-expressing cells with Sox9 deletion, combined with in vivo ChIP sequencing, uncovers a cancer-specific gene network regulated by Sox9 that promotes stemness, extracellular matrix deposition, and cytoskeleton remodeling while repressing epidermal differentiation. Our study identifies the molecular mechanisms regulated by Sox9 that link tumor initiation and invasion. [Display omitted] •Sox9 is required for BCC formation in a Wnt/β-catenin-dependent manner•ChIP-seq and microarray reveal a Sox9-controlled cancer-specific gene network•Sox9 promotes BCC stemness and self-renewal and inhibits differentiation•Sox9 controls ECM and cytoskeleton remodeling during tumor invasion Using mouse models of BCC, Larsimont et al. show that Sox9 is required for self-renewal of oncogene-expressing cells and BCC formation. Transcriptional profiling combined with ChIP sequencing uncovered a cancer-specific gene network regulated by Sox9 that promotes stemness, represses differentiation, and induces ECM and cytoskeleton remodeling required for tumor invasion.