Abstract

Signaling Mechanisms in Brain Tumor Initiating Cells

Neha Garg, Assistant Professor, IIT Mandi

Brain tumors represent leading cause of childhood and adult cancer mortality. Medulloblastoma (MB) is the most common malignant pediatric brain tumour. According to activation of different signaling pathways and varying clinical outcomes, MB is classified into 4 subgroups (Wnt, Shh, group 3, and group 4). Despite mutimodal therapy protocols, a subset of MB patients remains untreatable accounted due to presence of Cancer Stem Cells (CSCs). CD133 is one of the cell surface markers used to identify CSCs populations in MB, although the functional role of CD133 is still obscure. We hereby identified STAT3 as activated/enriched in CD133 positive MB CSCs compared with CD133 negative cells. Our study shows that STAT3 activation in MB CSCs may be a key-initiating event in driving tumorigenesis and regulating c-Myc, a pathway activated in group 3 MB. Before studying cancer stem cells, we have deciphered some of the signaling mechanisms in normal neural stem cells (NSCs). In spite of our good understanding of the mechanisms regulating the expression of these stemness drivers, there is incomplete knowledge of their target genes and of how the resulting regulatory network operates in order to determine stem cell features. MicroRNAs (miRNAs) have emerged as important players in the control of stem cell behaviour. This study allowed us to identify specific miRNAs controlled by Nanog, including miR-17-92 cluster. We identified a previously unsuspected backward arm of the Nanog/ p53 pathway cross-regulation of stemness. Our next work demonstrated that aggressive modulation of this cluster could regulate the pathogenesis of pediatric high-grade glioma (pHGG). Finally, the role of miR-21 will be discussed in lung derived brain metastasis.