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

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

doi:10.1016/j.stem.2015.05.008

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

Cell Stem Cell. 2015 Jul 2;17(1):60-73. doi: 10.1016/j.stem.2015.05.008. Epub 2015 Jun 18.

Authors

Jean-Christophe Larsimont¹, Khalil Kass Youssef¹, Adriana Sánchez-Danés¹, Vijayakumar Sukumaran¹, Matthieu Defrance², Benjamin Delatte², Mélanie Liagre¹, Pieter Baatsen³, Jean-Christophe Marine⁴, Saskia Lippens⁵, Christopher Guerin⁵, Véronique Del Marmol⁶, Jean-Marie Vanderwinden¹, Francois Fuks², Cédric Blanpain⁷

Affiliations

¹ Université Libre de Bruxelles, IRIBHM, Brussels 1070, Belgium.
² Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, Brussels 1070, Belgium.
³ EM-Facility EMoNe, VIB BIO Imaging Core, Center for Human Genetics Katholieke Universiteit Leuven, Leuven 3000, Belgium.
⁴ Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, Leuven 3000, Belgium.
⁵ Inflammation Research Center, Image Core Facility, VIB, Ghent 9052, Belgium; VIB Bio Imaging Core, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium.
⁶ Department of Dermatology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium.
⁷ Université Libre de Bruxelles, IRIBHM, Brussels 1070, Belgium; WELBIO, Université Libre de Bruxelles, Brussels 1070, Belgium. Electronic address: cedric.blanpain@ulb.ac.be.

PMID: 26095047
DOI: 10.1016/j.stem.2015.05.008

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actin Cytoskeleton / physiology
Animals
Carcinogenesis
Carcinoma, Basal Cell / etiology
Carcinoma, Basal Cell / genetics
Carcinoma, Basal Cell / physiopathology
Cell Adhesion
Cell Self Renewal / genetics
Cell Self Renewal / 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
Receptors, G-Protein-Coupled / physiology
SOX9 Transcription Factor / genetics
SOX9 Transcription Factor / physiology*
Signal Transduction
Skin Neoplasms / etiology
Skin Neoplasms / genetics
Skin Neoplasms / physiopathology
Smoothened Receptor

Substances

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

Associated data

GEO/GSE68613
GEO/GSE68755