Identification and functional validation of proteins involved in tumorigenesis are essential steps toward advancing cancer precision medicine.

In The Journal of Clinical Investigation researchers from the VIB–KU Leuven Center for Cancer Biology together with colleagues from INSERM (France) now report the important role for FES in the initiation and progression of melanoma that is notoriously quick to metastasize and that responds poorly to existing cancer treatments. Unexpectedly the expression of FES, which encodes a kind of protein better known for their ability to promote cancer development–, is lost in a large fraction of human melanoma. The researchers also identified a pharmacological way through which FES expression can be restored in human melanoma. This can be the first step in a novel therapeutic strategy against melanoma.

The fact that melanoma often exhibits UV–induced genetic alterations makes it, among other features, a very complex disease to study. Jean–Christophe Marine and others developed mouse models recapitulating some of the key histopathological features of the human disease.

Importantly, the mouse melanoma lesions are far less complex than their human counterparts. Taking advantage of these ‘simplified’ versions of melanoma, the researchers identified a dozen of new genes that are likely to play keyroles in the initiation and/or progression of human melanoma. To further validate their findings, they studied the role of one of the genes, namelyFES, and established its important contribution to the development of both mouse and human melanoma.

Previous research identified FES as an ‘oncogene’ – a gene that is able to transform a normal cell into a cancer cell under certain conditions – in leukemia, for example. However, its role in melanoma appears very different. Jean–Christophe: “To our surprise we obtained clear evidence that FES strongly suppresses melanoma growth and viability. Its expression is silenced in more than 30% of human melanoma lesions.

Importantly, we showed that FES deletion in mice accelerated the growth of melanoma tumors.” The team also showed that FES modulates the WNT signaling pathway. This key cancer pathway is activated in virtually all melanoma, but the mechanisms that contribute to this activation remain largely unclear. So this study provides one route through which this pathway is activated in about 30% of the cases.

The researchers also identified a pharmacological way of restoring the expression of FES in human melanoma. The approach involved the use of epigenetic drugs that promote DNA demethylation; some of which are currently tested in clinical trials for melanoma. It will be interesting to assess whether the efficacy of these drugs can be linked, at least partly, to restoration of FES expression. Jean–Christophe: “We will definitely further explore this new putative therapeutic strategy. Importantly, in the same time our data raise concerns about ongoing clinical trials with broad spectrum tyrosine kinase inhibitors. Some of these inhibitors inactivate FES and therefore may lead to undesired effects.”

This study is the result of a fruitful collaboration between the VIB labs of Jean–Christophe Marine and Diether Lambrechts and the lab of Paulo De Sepulveda of the French National Institute of Health and Medical Research (INSERM). Jean–Christophe: “This project was spearheaded by Michael Olvedy, who worked under the supervision of myself (promotor) and Diether Lambrechts (co–promoter) within the frame of the VIB international PhD program. The highthroughput DNA sequencing capabilities of the Diether Lambrechts lab was critical to the discovery of altered genes in mouse melanomas. And finally, Paulo Sepulveda was a key collaborator that assisted us in investigating the role of FES in tumor formation in vitro.”