GSE117620
Systems-level analyses reveal a convergent pathway for progression of diffuse astrocytoma and potential role for resveratrol in delaying high-grade transformation
We assembled genome-wide gene regulatory networks (“modules”) that are differentially co-expressed between grade II and grade III IDH1-mutated astrocytomas in order to identify drivers of astrocytoma progression. We prioritized module M2 as a candidate module regulating glioma transformation on the basis that the module was enriched for cancer predisposition genes and had a pattern of expression in human glioma samples associated with both clinical progression and genomic aberrations in known cancer genes. M2 was functionally enriched for genes related to cell cycle regulation, and a genome-wide reverse engineering approach predicted the known cell cycle regulators FoxM1, B-Myb, and E2F2 as key transcriptional regulators of this module. Using separate drug-induced transcriptional perturbation data, we predicted that the naturally occurring polyphenol resveratrol down-regulates multiple nodes of M2. Transcriptional modulation of M2 by resveratrol and its predicted growth inhibitory effects was experimentally confirmed in vitro using low-passage primary human astrocytoma cells, including at nanomolar concentrations of resveratrol achievable in human cerebral spinal fluid from oral dosing. Overall design: Primary anaplastic astrocytoma cells (TB98) were treated with 20uM, 10nM and 2nM resveratrol for 24h