Identifying the genes that control glioblastoma initiation and growth

Overview

Glioblastoma is the most common primary malignant brain tumour in adults, with around 2,500 people diagnosed every year in the UK.

The prognosis is bleak for those affected. Glioblastoma is a grade 4 tumour, meaning that it grows and spreads quickly. It is difficult to remove surgically because it infiltrates the brain, with finger-like tentacles that often wrap around vital brain structures.

Following surgery to remove the bulk of the tumour, radiation and chemotherapy are used in an effort to slow the growth of remaining tumour. But glioblastomas are aggressive tumours and often appear resistant to treatment or quickly recur.

Only 20 per cent of glioblastoma patients survive more than one year from diagnosis, and only three per cent survive more than three years. New treatments are desperately needed.

‍Read more: Brain tumours

Targeting brain cancer stem cells in glioblastoma

Cancer stem cells (CSCs) are a group of cells within a tumour that are particularly resistant to therapy. Even if most other tumour cells are eradicated, the CSCs can remain and cause the tumour to re-grow.

Understanding the properties of these CSCs – and finding a way to destroy them – could therefore hold the key to the more effective treatment of tumours. Yet, despite ongoing research efforts from teams around the world, knowledge in this area remains very limited.

Dr Barros was awarded this funding for a project that built on previous work in which she used a sophisticated system to model aspects of human glioblastoma stem cells and tumour development using the fruit fly Drosophila. This model enables visualisation of the CSCs at the time they originate inside the brain, enabling identification of early cellular and molecular changes even prior to tumour growth onset. The team identified a set of molecules that are differently expressed in CSCs and normal brain cells, more than 70% of which have matching molecules in humans. This was the starting point for the new study.

Working in collaboration with colleagues from Derriford Hospital in Plymouth and the Medical Research Council Centre for Regenerative Medicine in Edinburgh, Dr Barros set out to decipher the mechanisms responsible for the formation and development of CSCs in glioblastoma.

By examining the early events of tumour formation, the team identified striking changes in CSCs, including in metabolism and in a process called ribogenesis, through which new proteins are made. They also found that - out of the molecules tested in the Drosophila model - a majority are also abnormally expressed in human glioblastoma and are highly enriched in the glioblastoma stem cells. Through detailed analysis of the function of three selected molecules they demonstrated roles in the over-proliferation of brain tumour cells, tumour growth and maintenance.

In a recent publication in the journal EMBO Reports¹, the team present the new insights on initial steps of brain tumour formation and a mechanism whereby one of the molecules identified, HEATR1, works with a main growth regulator named MYC and is needed for increased ribogenesis critical for the onset of tumour growth.

This work has revealed human genes and mechanisms underlying the early stages of brain tumour development, opening new research directions that are already being pursued by Dr Barros and team. It exposes potential targets for future enhanced glioblastoma therapies. The identification, design and validation of drugs that can inhibit the action of these molecules, or ways to manipulate them genetically, are next steps towards patient benefit.

1. https://www.embopress.org/doi/full/10.1038/s44319-023-00017-1