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Glioblastoma (GBM) is known as an intractable, highly heterogeneous tumor encompassing multiple subclones, each supported by a distinct glioblastoma stem cell (GSC). The contribution of GSC genetic and transcriptional heterogeneity to tumor subclonal properties is debated. In this study, we describe the systematic derivation, propagation, and characterization of multiple distinct GSCs from single, treatment-naive GBMs (GSC families). The tumorigenic potential of each GSC better correlates with its transcriptional profile than its genetic make-up, with classical GSCs being inherently more aggressive and mesenchymal more dependent on exogenous growth factors across multiple GBMs. These GSCs can segregate and recapitulate different histopathological aspects of the same GBM, as shown in a paradigmatic tumor with two histopathologically distinct components, including a conventional GBM and a more aggressive primitive neuronal component. This study provides a resource for investigating how GSCs with distinct genetic and/or phenotypic features contribute to individual GBM heterogeneity and malignant escalation. [Display omitted] • Distinct GSCs can be derived from single GBMs by different growth factor cocktails • GSCs segregate different RTK expression and gene amplifications • GSCs segregate distinct transcriptional profiles, each related to different malignancy • GSCs with a neural progenitor profile recapitulate the GBM primitive neuronal component De Bacco et al. devise a methodology to propagate distinct glioblastoma stem-like cells (GSCs) from individual tumors, stably segregating different features coexisting in the original tumor. The GSCs' transcriptional profile is a superior indicator of their tumorigenicity compared with their genetic make-up, uncovering diverse phenotypes that drive intratumoral heterogeneity. [ABSTRACT FROM AUTHOR]

In glioblastoma (GBM), the most frequent and lethal brain tumor, therapies suppressing recurrently altered signaling pathways failed to extend survival. However, in patient subsets, specific genetic lesions can confer sensitivity to targeted agents. By exploiting an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo , here, we identify a human GBM subset (∼9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. ERBB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype. Overexpressed ERBB3 behaves as a specific signaling platform for fibroblast growth factor receptor (FGFR), driving PI3K/AKT/mTOR pathway hyperactivation, and overall metabolic upregulation. As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy. [Display omitted] • Total of ∼9% of human GBMs feature ERBB3 overexpression and nuclear accumulation • ERBB3 overexpression is sustained by miR-205 inactivation • Overexpressed ERBB3 is activated by FGFR and upregulates cell metabolism • ERBB3 targeting by a specific antibody inhibits growth of ERBB3-overexpressing GBMs Taking advantage of an integrated model based on patient-derived stem-like cells, De Bacco et al. identify a GBM subset characterized by ERBB3 overexpression, driven by an inheritable mechanism of miR-205 inactivation. By upregulating cell metabolism, overexpressed ERBB3 provides a selective advantage and a liability to be exploited for targeted therapy. [ABSTRACT FROM AUTHOR]