Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma

Abstract

Summary Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.

Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma

“…DIPG primary tumor and cell culture samples exhibit expression of the protein tyrosine phosphatase receptor type ζ gene PTPRZ1 (Grasso et al, 2015; Nagaraja et al, 2017; Fig S5C). Robust shRNA-mediated knockdown of PTPRZ1 expression in DIPG cells (Figure S5D) substantially decreases baseline invasion (Figure S5E) and also mildly decreases cell viability (Figure S5F).…”

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

“…Samples were processed and analyzed as previously described 12 with minor modifications as indicated below:…”

“…Performed in biological triplicate. d , mRNA expression levels of ADAM10 in primary tumor and cultures of DIPG by RNA-seq with values reported as FPKM 12,28 (left; n =8 primary samples, n =7 culture samples) and in 493 individual adult glioblastoma samples from TCGA 29 (right). Values are reported as robust multi-array averages (RMA; right).…”

“…Genes involved in cell proliferation were upregulated, as were numerous genes known to promote malignancy in glioma, including PDGFA 8–10 , TTYH1 11 and several potassium channel genes 12 (Extended Data Fig. 3).…”

Neuronal activity in the glioma microenvironment

“…While the glioma cell of origin remains unconfirmed and openly debated, accumulating research suggests that glioma may arise from neural stem or precursor cells of the oligodendroglial lineage, specifically oligodendrocyte precursor cells (OPCs), pre-OPCs or earlier neural precursor cells (NPCs) (Galvao et al, 2014; Liu et al, 2011; Monje et al, 2011; Wang et al, 2009; Nagaraja et al, 2017). The known influence of active neurons on the proliferation, differentiation, and/or function of the cells from which glioma is thought to arise suggest that parallel mechanisms could play a role in glial cancers if co-opted for the promotion of tumor growth and progression.…”