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 will provide a therapeutic goal for the deadly, treatment-resistant brain cancer glioblastoma multiforme (GBM).

The gene, P300, enables GBM cells which have been damaged by radiation therapy to recuperate 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, in line with the researchers, who conducted their studies in mouse models and in human GBM cells. Their results appear online in Nature Communications.

Although glioblastoma is taken into account rare – about 13,000 latest cases are expected to be diagnosed in the US this 12 months, in line with the National Brain Tumor Society – it’s essentially the most common primary brain tumor in adults. There isn’t any known cure, and the typical length of survival is measured in months. GBM cells and their precursors, glioma stem cells (GSC), quickly adapt and recuperate from injury, so chemotherapy and radiation therapy, which can initially slow a tumor’s progress, can ultimately contribute to growth and reoccurrence..

By performing single-cell transcriptomic sequencing, which might discover 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 forms of cells which are normally present in blood vessels (vascular endothelial-like cells and pericyte-like cells). They found that these converted cells promoted tumor growth and post-treatment reoccurrence. The conversion was led to by changes inside specific vascular gene regions in a process mediated by the gene P300, or P300 HAT (histone acetyltransferase).

Our findings show on the single-cell level that ‘radiation-stress’ alters the functional states of glioma cells, but as a substitute of reconstituting the vascular system to hold blood supply, as has sometimes been theorized, these converted cells provide trophic support that allows the cancer cells to survive and grow under the hostile conditions created by radiation.”

Harley Kornblum, M.D., Ph.D., Senior Creator, Researcher, 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 dam the phenotypic conversion. This implies that small molecules that inhibit P300 HAT activity could also be useful in stopping tumor growth and adaptive resistance of GBM,” said Dr. Sree Deepthi Muthukrishnan, Assistant Project Scientist and the primary writer of the study.

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

Source:

University of California – Los Angeles Health Sciences

Journal reference:

Muthukrishnan, S.D., et al. (2022) P300 promotes tumor reoccurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells. Nature Communications. doi.org/10.1038/s41467-022-33943-0.