IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy

Georgette Tanner, Rhiannon Barrow, Shoaib Ajaib, Muna Al-Jabri, Nazia Ahmed, Steven Pollock, Martina Finetti, Nora Rippaus, Alexander F Bruns, Khaja Syed, James A Poulter, Laura Matthews, Thomas Hughes, Erica Wilson, Colin Johnson, Frederick S Varn, Anke Brüning-Richardson, Catherine Hogg, Alastair Droop, Arief GusnantoMatthew A Care, Luisa Cutillo, David R Westhead, Susan C Short, Michael D Jenkinson, Andrew Brodbelt, Aruna Chakrabarty, Azzam Ismail, Roel G W Verhaak, Lucy F Stead

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur.

Results: Using RNA sequencing data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumors, we identify two responder subtypes based on longitudinal changes in gene expression. In two thirds of patients, a specific subset of genes is upregulated from primary to recurrence (Up responders), and in one third, the same genes are downregulated (Down responders), specifically in neoplastic cells. Characterization of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms that are associated with distinct changes in the tumor microenvironment. In Up responders, recurrent tumors are enriched in quiescent proneural GBM stem cells and differentiated neoplastic cells, with increased interaction with the surrounding normal brain and neurotransmitter signaling, whereas Down responders commonly undergo mesenchymal transition. ChIP-sequencing data from longitudinal GBM tumors suggests that the observed transcriptional reprogramming could be driven by Polycomb-based chromatin remodeling rather than DNA methylation.

Conclusions: We show that the responder subtype is cancer-cell intrinsic, recapitulated in in vitro GBM cell models, and influenced by the presence of the tumor microenvironment. Stratifying GBM tumors by responder subtype may lead to more effective treatment.

Original languageEnglish
Article number45
Number of pages29
JournalGenome Biology
Volume25
Issue number1
DOIs
Publication statusPublished - 7 Feb 2024

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