June 15, 2012

Identification of a novel target for glioblastoma treatment

A recent study from scientists of Brian Hemmings group has identified a novel target for the treatment of malignant brain tumors. The scientists found that the Mer receptor tyrosine kinase (MerTK) is highly expressed in human brain tumors but absent from normal adult brain tissue. MerTK not only increases the invasive potential of brain tumor-derived cells but also promotes their survival when treated with chemotherapeutics. Conversely, the authors demonstrate that loss of MerTK strongly reduces the invasive capacity of tumor cells, making it an attractive target for future brain tumor therapies.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor in adults. GBM tumor cells multiply at high rates and readily invade adjacent healthy brain tissue. The mean survival of a patient diagnosed with GBM amounts to 14 months, also reflecting the high incidence of resistance against standard therapies. Alarmingly, radio- and chemotherapies, routinely used to treat GBM patients after surgical removal of the primary tumor, have been reported to increase the aggressiveness of residual tumor cells resulting in the recurrence of secondary GBMs.

In search of alternative therapeutic approaches, scientists from the group of Brian Hemmings at the Friedrich Miescher Institute for Biomedical Research teamed up with clinicians and pathologists. They profiled human GBM tumors to define common molecular signatures with the ultimate goal to specifically target the tumor cells while sparing their healthy neighbors. In this context, Yuhua Wang, a collaborator in Hemmings laboratory, and her colleagues have discovered that MerTK is strongly expressed in malignant gliomas but absent from normal brain. To study the underlying mechanism, they turned to established GBM-derived cell lines and found that MerTK is not expressed in these cells. However, when they analyzed GBM-derived spheres – cell aggregates that are grown in serum-free medium and thus resemble the actual tumor situation more closely – they found high MerTK levels. Subsequently, Wang established that MerTK was essential to maintain the rounded morphology and invasive capacity of GBM cells. All effects were reversed when a mutant form of MerTK was used that could no longer undergo phosphorylation at three critical residues. Further experiments revealed that MerTK drives GBM cell invasion by regulating actomyosin contractility, thus helping the invading cell to “squeeze through” small spaces into the surrounding brain tissue. Lastly, the scientists discovered that MerTK protein expression was induced by DNA damage and protected glioma cells against cytotoxic insults. This last finding suggests that MerTK is – at least in part –responsible for glioma cell survival and enhanced invasion after radiotherapy.

“Radiotherapy is the most commonly used therapeutic modality for malignant gliomas; it significantly prolongs the patients’ life expectancy”, explains Wang. “But although many gliomas initially respond, all of them invariably recur, even in combination with surgery and chemotherapy, a phenomenon we still don’t fully understand. MerTK, which is overexpressed in 90% of the analyzed GBM tumors, appears to support characteristics that are vital for tumor cells, namely resistance against DNA-damaging agents and invasion. We therefore propose MerTK as a potential new target for the treatment of malignant gliomas.”

Original publication
Wang Y, Moncayo G, Morin P Jr, Xue G, Grzmil M, Lino MM, Clément-Schatlo V, Frank S, Merlo A, Hemmings BA (2012). Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme. Oncogene [Epub ahead of print]

About Yuhua Wang and Brian Hemmings
Yuhua Wang is a collaborator in Brian Hemmings research team. Brian Hemmings is a group leader at the FMI. He is interested in targeting novel kinases involved in the development and progression of glioblastoma, ovarian cancer and lymphoma.
» More about Brian Hemmings

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