Luxembourg Institute of Health Research Sheds New Light on Glioblastoma Invasiveness

The Luxembourg Institute of Health (LIH) has identified a protein that activates genes involved in malignant brain tumour growth and expansion.     

Researchers from the NORLUX Neuro-Oncology Laboratory at the LIH Department of Oncology (DONC) explored the molecular mechanisms responsible for the ability of Glioblastoma (GBM) to infiltrate and spread to healthy brain tissue. They brought forward the novel role of the AN1-Type Zinc Finger protein 3 (ZFAND3) in activating several genes that stimulate the adhesion and penetration of GBM cells in the surrounding parenchyma, the functional tissue in the brain. 

One of the hallmarks of GBM, the most aggressive type of brain cancer, is its highly invasive capacity, which leads to its expansion into the neighbouring normal brain tissue. GBM cells insinuate themselves in the space of the neural tissue and migrate along blood vessels to more distant locations where they then metastasise. "Stray" cancer cells can therefore escape surgical resection, radio- and chemotherapy, thereby accounting for the limited success of current treatment approaches and for the poor patient prognosis observed. Novel molecular targets that regulate invasion and that can be leveraged during drug development are therefore a priority in modern-day oncology.

“In this context, we sought to elucidate the genes responsible for GBM invasiveness and the specific molecules that ‘switch’ them on”, commented Prof Simone Niclou, Director of the LIH DONC and corresponding author of the publication.

Using a molecular biology technique commonly used to uncover the function of a gene and its effects on the functioning of the cell, the scientists found a set of genes associated with GBM proliferation, some of which previously known to be involved in invasion and metastasis. This selection was further narrowed down by analysing the differences in their expression in non-invasive versus invasive GBM cells. The team found the gene coding for the ZFAND3 to be significantly more active in invasive cells compared to non-invasive cells. Invasive cells located in the periphery of the tumours consequently presented higher amounts of the resulting ZFAND3 protein.

“When we deactivated the ZFAND3 gene in highly invasive GBM cells, we observed that colonisation of healthy tissue was significantly impaired, indicating that ZFAND3 plays a key role in promoting GBM invasiveness”, explained Dr Anne Schuster, first author of the publication.

Eliane Klein, second author of the study, added: “Similarly, when we over-activated the ZFAND3 gene in non-invasive GBM cells in mice, we noticed that the tumour lost the well-defined growth pattern typical of non-invasive tumours, and that the number of cells escaping the primary tumourincreased considerably, further confirming that ZFAND3 confers invasion potential to GBM cells even if they were initially non-invasive”.

The team went a step further and sought to unravel the precise mechanism behind the ability of ZFAND3 to induce infiltration. They noted that ZFAND3 acts directly in the nucleus of the cell, where it interacts closely with several other proteins to stimulate the activation of a series of invasion-related genes, thereby resulting in the aggressive behaviour that characterises highly invasive GBM cells.

Prof Niclou concluded: “In essence, our work has brought forward ZFAND3 as a novel key regulator involved in the malignancy of GBM, thereby providing a new and much needed potential target against which future drugs may be directed”. 

The findings were published in December 2020 in the prestigious journal "Nature Communications", with the full title “AN1-type zinc finger protein 3 (ZFAND3) is a transcriptional regulator that drives Glioblastoma invasion”.