Abstract
A shift to a mesenchymal phenotype characterizes recurrence in glioblastoma and is mediated by AP1.
Major Finding: A shift to a mesenchymal phenotype characterizes recurrence in glioblastoma and is mediated by AP1.
Concept: Increased T-cell abundance at recurrence is prognostic and correlates with hypermutation status.
Impact: This single-cell atlas of glioblastoma provides an understanding of therapy-induced selection pressure.
In glioblastoma (GBM), a lack of selection pressure for DNA mutations in recurrent disease has recently been demonstrated. Additionally, single-cell lineage tracing has revealed a high level of plasticity in GBM cells along with transitions between cellular states, but it remains undetermined if this phenotype switching is the predominant form of escape from precision therapies in GBM. To determine the selection pressure of standard therapies like temozolomide chemotherapy, ionizing radiation (IR), and surgical resection in GBM, Wang, Jung, Babikir, and colleagues profiled 86 matched primary-recurrent specimens from patients with GBM using single-nucleus RNA sequencing, single-cell assay for transposase-accessible chromatin, spatial transcriptomic/proteomic assays, and exome sequencing to provide a single-cell multiomic atlas for GBM under therapy. A shift to a mesenchymal (MES) cell state was found to characterize recurrent GBM, and activator protein 1 (AP1) was enriched in this population in which it regulates all previously described hallmarks of the MES phenotype through cis-regulatory enhancers. IR induced expression of AP1 in GBM as well as MES hallmark genes, including those mediating inflammation, IR resistance, and invasiveness, suggesting this as a potential mechanism of therapy escape. Moreover, screening of genes from the AP1 regulome against databases of known drug interactions revealed that three drugs targeting an AP1-regulated gene had in vitro cytotoxic activity, which supports the therapeutic benefit of targeting the AP1 regulome. Furthermore, investigation into the effects of standard of care on immune cells in the GBM microenvironment showed T-cell abundance at recurrence was correlated with increased overall survival and that T-cell infiltration was linked to hypermutation status. Finally, spatial analyses of GBM tissue revealed potential cell-extrinsic therapeutic targets including IGF1, PTN, and WNT3A, where treatment with these recombinant ligands increased cell proliferation. In summary, this study provides a single-cell atlas of GBM under therapy that allowed for evaluation of the genetic and molecular mechanisms behind the MES transition at recurrence as well as revealed potential targets for therapeutic development.
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