A coregulatory influence map of glioblastoma heterogeneity and plasticity - From cells in vitro to tumors and back again

Abstract

We present GBM-cRegMap, an online resource providing a comprehensive coregulatory influence network perspective on glioblastoma (GBM) heterogeneity and plasticity. Using representation learning algorithms, we derived two components of this resource: GBM-CoRegNet, a highly specific coregulatory network of tumor cells, and GBM-CoRegMap, a unified network influence map based on 1612 tumors from 16 studies. As a widely applicable closed-loop system connecting cellular models and tumors, GBM-cRegMap will provide the GBM research community with an easy-to-use web tool (https://gbm.cregmap.com) that maps any existing or newly generated transcriptomic "query" data to a reference coregulatory network and a large-scale manifold of disease heterogeneity. Using GBM-cRegMap, we demonstrated the synergy between the two components by refining the molecular classification of GBM, identifying potential key regulators, and aligning the transcriptional profiles of tumors and in vitro models. Through the amalgamation of a vast dataset, we validated the proneural (PN)-mesenchymal (MES) axis and identified three subclasses of classical (CL) tumors: astrocyte-like (CL-A), epithelial basal-like (CL-B), and cilium-rich (CL-C). We revealed the CL-C subclass, an intermediate state demonstrating the plasticity of GBM cells along the PN-MES axis under chemotherapy. We identified key regulators, such as PAX8, and NKX2.5, involved in TMZ resistance. Notably, NKX2.5, more expressed in higher-grade gliomas, negatively impacts patient survival and regulates genes involved in glucose metabolism. O_FIG O_LINKSMALLFIG WIDTH=152 HEIGHT=200 SRC="FIGDIR/small/609303v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@c7a401org.highwire.dtl.DTLVardef@e0681corg.highwire.dtl.DTLVardef@d31f55org.highwire.dtl.DTLVardef@ae350f_HPS_FORMAT_FIGEXP M_FIG C_FIG