Abstract
Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear.Experimental Design: We performed in silico screening and in vitro validation studies through Western blotting, qRT-PCR for treatment of WNT and SHH signaling inhibitors, and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice.Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through miRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacologic blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice.Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation. Clin Cancer Res; 24(2); 383-94. ©2017 AACR.
Highlights
As the most prevalent primary intrinsic brain tumor, glioblastoma (GBM) is a universally lethal cancer with a median survival less than 15 months despite multimodal therapy [1]
Collectively, our results suggested that Inhibitor of differentiation 1 (ID1) simultaneously regulates stemness through WNT and SHH signaling and differentiation through bone morphogenetic protein receptor (BMPR)-mediated differentiation signaling in glioblastoma stem cells (GSCs), informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation
Transcriptional profiling of ID1 and lineage differentiation To explore the relationship between the inhibitor of differentiation (ID) family and lineage differentiation, we first examined the correlation between four ID family members (ID1–4) and lineage differentiation signatures including astrocytic, oligodendrocytic, and neuronal lineages [45] in multiple available gene expression patient datasets, including Gleize, Gravendeel, Pola.network, and TCGA GBM-low grade glioma (GBM-LGG) datasets [34,35,36,37]
Summary
As the most prevalent primary intrinsic brain tumor, glioblastoma (GBM) is a universally lethal cancer with a median survival less than 15 months despite multimodal therapy [1]. GBMs contain strikingly heterogeneous cellular populations with diverse transcriptional profiles, morphology, invasive potential, Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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