Single-cell transcriptomics identifies a gene as a potential target in treatment-resistant brain cancer

Research led by doctors and scientists at UCLA Jonsson Comprehensive Cancer Center and the UCLA Jane & Terry Semel Institute for Neuroscience & Human Behavior have identified a gene that may provide a therapeutic target for the deadly, treatment-resistant brain cancer glioblastoma multiforme (GBM).

The gene, P300, enables GBM cells that have been damaged by radiation therapy to recover by rearranging DNA,  and initiating a molecular mechanism that refortifies tumor cells for growth and survival. Blocking P300 disrupted its ability to set this process in motion, according to the researchers, who conducted their studies in mouse models and in human GBM cells.

Although glioblastoma is considered rare – about 13,000 new cases are expected to be diagnosed in the United States this year, according to the National Brain Tumor Society – it is the most common primary brain tumor in adults. There is no known cure, and the average length of survival is measured in months. GBM cells and their precursors, glioma stem cells (GSC), quickly adapt and recover from injury, so chemotherapy and radiation therapy, which may initially slow a tumor’s progress, can ultimately contribute to  growth and recurrence..

By performing single-cell transcriptomic sequencing, which can identify molecular changes in cancerous cells, the UCLA-led research team showed that radiation therapy-induced stress promotes phenotypic conversion of glioma stem cells to resemble two types of cells that are normally found in blood vessels (vascular endothelial-like cells and pericyte-like cells). They found that these converted cells promoted  tumor growth and post-treatment recurrence. The conversion was brought about by changes within specific vascular gene regions in a process mediated by the gene P300, or P300 HAT (histone acetyltransferase).

Single-cell sequencing reveals the diverse functional states of glioma cells post-radiation

Fig. 1

a UMAP plot of cell clusters from control (0 Gy) and 2- and 7-days radiated (8 Gy) fractions. b Histogram shows the number of cells per cluster in each group. c Heatmap shows Louvain clustering of co-expressed gene network modules and EnrichR GO_terms associated with each cluster. Each subgroup is highlighted by a black box. d Pseudotime trajectory analysis, subgroups are highlighted in colored circles and their functional cell states indicated in the inset. e Heatmap of average expression of markers of proliferation, glioma stem cells (GSC), Neural crest-mesenchymal stem cells (NC-MSC), pericytes, mesodermal and endothelial cells. f Heatmap of normalized enrichment scores (NES) of gene sets in glioma cells 2- and 7-days post-radiation. N = 3 biological replicates and only gene sets with p < 0.05 are shown. g Heatmap of relative expression of endothelial, pericyte and stemness genes in control and radiated cells. N = 3 independent experiments. *, ** indicates p < 0.05, p < 0.005, unpaired two-tailed t-test.

“Our findings show at the single-cell level that ‘radiation-stress’ alters the functional states of glioma cells, but instead of reconstituting  the vascular system to carry blood supply, as has sometimes been theorized, these converted cells provide trophic support that enables the cancer cells to survive and grow under the hostile conditions created by radiation,” said senior author Harley Kornblum, M.D., Ph.D., a researcher at the UCLA Jonsson Comprehensive Cancer Center and the UCLA Brain Research Institute.

“Just as P300 plays a key role in changing the molecular landscape of glioma stem cells, inhibiting the gene’s function appears to block the phenotypic conversion. This suggests that small molecules that inhibit P300 HAT activity may be useful in preventing  tumor growth and adaptive resistance of GBM,” said Dr. Sree Deepthi Muthukrishnan, Assistant Project Scientist and the first author of the study.

While the authors were able to identify some candidate factors expressed by the vascular-like cells and their experiments show those factors’ potential role in promoting proliferation of radiated tumor cells, they say  that further studies will be needed to fully uncover the underlying mechanisms at play. Importantly though, the factors that mediate the trophic actions of radiation-induced vascular-like cells would likely be targets for potential therapeutic intervention to prevent GBM relapse.

SourceUCLA Health

Muthukrishnan SD, Kawaguchi R, Nair P, Prasad R, Qin Y, Johnson M, Wang Q, VanderVeer-Harris N, Pham A, Alvarado AG, Condro MC, Gao F, Gau R, Castro MG, Lowenstein PR, Deb A, Hinman JD, Pajonk F, Burns TC, Goldman SA, Geschwind DH, Kornblum HI. (2022) P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells. Nat Commun 13(1):6202. [article]

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