Glioblastoma (GBM) constitutes the most common and aggressive primary brain tumor. To better understand how GBM evolves we analyzed longitudinal genomic and transcriptomic data of 114 patients. The analysis reveals a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern together with estimates of evolutionary rates suggest that the relapse associated clone typically preexisted years before diagnosis. 15% of tumors present hypermutations at relapse in highly expressed genes with a clear mutational signature. We find that 11% of recurrent tumors harbor mutations in LTBP4, a protein binding to TGF-β. Silencing LTBP4 in GBM cells leads to TGF-β activity suppression and decreased proliferation. In IDH1-wild-type recurrent GBM, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-β pathway as a potential therapeutic target in GBM.
SUMMARY
Unresectable glioblastoma (GBM) cells in the invading tumor edge can act as seeds for recurrence. The molecular and
phenotypic properties of these cells remain elusive. Here, we report that the invading edge and tumor core have two distinct types
of glioma stem-like cells (GSCs) that resemble proneural (PN) and mesenchymal (MES) subtypes, respectively. Upon exposure to
ionizing radiation (IR), GSCs, initially enriched for a CD133
+
PN signature, transition to a CD109
+
MES
subtype in a C/EBP-β-dependent manner. Our gene expression analysis of paired cohorts of patients with primary and
recurrent GBMs identified a CD133-to-CD109 shift in tumors with an MES recurrence. Patient-derived
CD133
−
/CD109
+
cells are highly enriched with clonogenic, tumor-initiating, and
radiation-resistant properties, and silencing CD109 significantly inhibits these phenotypes. We also report a conserved regulation
of YAP/TAZ pathways by CD109 that could be a therapeutic target in GBM.
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