ABSTRACT
Glioblastomas (GBM) are lethal primitive brain tumours characterized by a strong intra-tumour heterogeneity. We observed in GBM tissues the coexistence of functionally divergent micro-territories either enriched in more differentiated and non-mitotic cells or in mitotic undifferentiated OLIG2 positive cells while sharing similar genomic abnormalities. Understanding the formation of such functionally divergent micro-territories in glioblastomas (GBM) is essential to comprehend GBM biogenesis, plasticity and to develop therapies. Here we report an unexpected anti-proliferative role of beta-catenin in non-mitotic differentiated GBM cells. By cell type specific stimulation of miR-302, which directly represses cyclin D1 and stemness features, beta-catenin is capable to change its known proliferative function. Nuclear beta-catenin accumulation in non-mitotic cells is due to a feed forward mechanism between DOCK4 and beta-catenin, allowed by increased GSK3-beta activity. DOCK4 over expression suppresses selfrenewal and tumorigenicity of GBM stem-like cells. Accordingly in the frame of GBM median of survival, increased level of DOCK4 predicts improved patient survival.
Subject(s)
GTPase-Activating Proteins/metabolism , Glioblastoma/pathology , MicroRNAs/metabolism , Neoplastic Stem Cells/pathology , beta Catenin/metabolism , Adult , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Brain/pathology , Cell Nucleus/metabolism , Cell Proliferation , Feedback, Physiological , GTPase-Activating Proteins/genetics , Glioblastoma/genetics , Glioblastoma/mortality , Glycogen Synthase Kinase 3 beta/genetics , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Male , Mice , Mice, Inbred NOD , MicroRNAs/genetics , Mitosis , Neoplastic Stem Cells/cytology , Oligodendrocyte Transcription Factor 2/metabolism , Primary Cell Culture , RNA, Small Interfering/metabolism , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Young Adult , beta Catenin/geneticsABSTRACT
Glioblastoma multiforme (GBM) is the most common form of primary brain tumor in adults, often characterized by poor survival. Glioma-initiating cells (GiCs) are defined by their extensive self-renewal, differentiation, and tumor initiation properties. GiCs are known to be involved in tumor growth and recurrence, and in resistance to conventional treatments. One strategy to efficiently target GiCs in GBM consists in suppressing their stemness and consequently their tumorigenic properties. In this study, we show that the miR-302-367 cluster is strongly induced during serum-mediated stemness suppression. Stable miR-302-367 cluster expression is sufficient to suppress the stemness signature, self-renewal, and cell infiltration within a host brain tissue, through inhibition of the CXCR4 pathway. Furthermore, inhibition of CXCR4 leads to the disruption of the sonic hedgehog (SHH)-GLI-NANOG network, which is involved in self-renewal and expression of the embryonic stem cell-like signature. In conclusion, we demonstrated that the miR-302-367 cluster is able to efficiently trigger a cascade of inhibitory events leading to the disruption of GiCs stem-like and tumorigenic properties.
Subject(s)
Glioma/genetics , MicroRNAs/genetics , Multigene Family/genetics , Neoplastic Stem Cells/pathology , Receptors, CXCR4/metabolism , Signal Transduction , Animals , Cell Line, Tumor , Cell Lineage , Cell Movement , Cell Proliferation , Cell Transformation, Neoplastic/pathology , Down-Regulation , Gene Expression Regulation, Neoplastic , Glioma/pathology , Humans , Mice , Neoplastic Stem Cells/metabolism , Receptors, CXCR4/genetics , SerumABSTRACT
Cancer cells frequently express genes normally active in male germ cells. ATAD2 is one of them encoding a conserved factor harbouring an AAA type ATPase domain and a bromodomain. We show here that ATAD2 is highly expressed in testis as well as in many cancers of different origins and that its high expression is a strong predictor of rapid mortality in lung and breast cancers. These observations suggest that ATAD2 acts on upstream and basic cellular processes to enhance oncogenesis in a variety of unrelated cell types. Accordingly, our functional studies show that ATAD2 controls chromatin dynamics, genome transcriptional activities and apoptotic cell response. We could also highlight some of the important intrinsic properties of its two regulatory domains, including a functional cross-talk between the AAA ATPase domain and the bromodomain. Altogether, these data indicate that ATAD2 overexpression in somatic cells, by acting on basic properties of chromatin, may contribute to malignant transformation.