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

Abstract

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.

• Authors: Jean-Christophe Larsimont, Khalil Kass Youssef, Adriana Sánchez-Danés, Vijayakumar Sukumaran, Matthieu Defrance, Benjamin Delatte, Mélanie Liagre, Pieter Baatsen, Jean-Christophe Marine, Saskia Lippens, Christopher Guerin, Véronique Del Marmol, Jean-Marie Vanderwinden, Francois Fuks, Cédric Blanpain
• Journal: Cell stem cell (Cell Stem Cell) Vol. 17 Issue 1 Pg. 60-73 (Jul 02 2015) ISSN: 1875-9777 [Electronic] United States
• PMID: 26095047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Hedgehog Proteins
• Receptors, G-Protein-Coupled
• SOX9 Transcription Factor
• Smo protein, mouse
• Smoothened Receptor
• Sox9 protein, mouse

Topics

• Actin Cytoskeleton (physiology)
• Animals
• Carcinogenesis
• Carcinoma, Basal Cell (etiology, genetics, physiopathology)
• Cell Adhesion
• Cell Self Renewal (genetics, physiology)
• Cell Transformation, Neoplastic (genetics)
• Extracellular Matrix (physiology)
• Female
• Gene Deletion
• Hedgehog Proteins (physiology)
• Humans
• Male
• Mice
• Mice, Knockout
• Mice, Transgenic
• Models, Biological
• Mutation
• Neoplasm Invasiveness
• Neoplastic Stem Cells (physiology)
• Oncogenes
• Receptors, G-Protein-Coupled (genetics, physiology)
• SOX9 Transcription Factor (genetics, physiology)
• Signal Transduction
• Skin Neoplasms (etiology, genetics, physiopathology)
• Smoothened Receptor