Melanoma is a particularly nasty type of skin cancer. It progresses and spreads very quickly, and in many cases it is resistant to chemotherapy. Currently, two VIB research groups are investigating melanoma. The group in Leuven is studying the interaction between the tumor suppressor p53 and MDM4, and how the disruption of this interaction might lead to improved cancer therapy. The Ghent-based group is looking into the epithelial to mesenchymal transition (EMT) process and the role it plays in cancer metastasis.
Melanoma is a cancer that originates from melanocytes, the cells that give our skin its color. By producing the pigment melanin, melanocytes protect our skin from DNA-damaging UV light. When these heavily pigmented cells mutate and give rise to cancer, a growing dark spot called a melanoma can be observed.
Melanoma is an especially aggressive and deadly type of cancer. Despite it being relatively uncommon among skin cancers (less than 2% of skin cancer cases), melanoma is responsible for the vast majority of skin cancer deaths. It is also one of the very few cancers with increasing incidence.
Luckily, Belgian scientists are studying the specifics of melanoma: its origins, its mechanisms and potential new treatments. Two VIB research groups are investigating melanoma, each with a unique and interesting approach. Here, we briefly present the research focuses of these groups, which are led by Professor Jean-Christophe Marine and Professor Geert Berx.
Jean-Christophe Marine (VIB/KU Leuven): Targeting MDM4
The research group of Prof. Marine at VIB/KUL focusses their melanoma research on the protein p53. Perhaps the most widely known tumor suppressor, p53 functions as a cancer shield by facilitating DNA repair activation and cell cycle regulation. The gene coding for p53 (TP53) is the most mutated gene in cancer, underlining its importance in tumorigenesis.
In contrast to other tumor types, melanoma cells contain relatively few p53 mutations. However, these tumor cells use another mechanism to block p53 function. MDM4 is a natural inhibitor of p53, and its overexpression can lead to cancer. This is also the most commonly observed mechanism in melanomas, representing over 65% of the cases.
For this reason, MDM4 is an interesting drug target. However, Prof. Marine’s group found that blocking its interaction with p53 is particularly challenging. Additionally, it was revealed that MDM4 can also cause cancer in a p53-independent manner. This led the group to tackle the problem from a different angle, shifting their focus to reducing the abundance of MDM4. MDM4 can be downregulated through the use of antisense oligonucleotides, reducing tumor growth and increasing tumor cell death, both in vitro and in vivo. This confirms MDM4 as an important drug target, not only in melanoma, but also in other types of cancer where p53 mutations are absent. Breast cancer, ovarian cancer, retinoblastoma and B-cell lymphoma might all benefit from anti-MDM4 therapy
Geert Berx (VIB/UGent): Hardwired melanocytes
The group of Prof. Berx specializes in the process of epithelial to mesenchymal transition (EMT), which is of huge importance in cell motility and migration. This cellular program is also initiated during cancer metastasis. Since melanoma patients frequently show multiple metastases, EMT is thought to be central in melanoma development. Prof. Berx explains:
“From an embryological perspective, melanocytes originate from neural crest cells, which then undergo EMT and differentiate into various cell types. It is suspected that the EMT process is hardwired into melanocytes because of their development from neural crest cells. When mutations then bring the cellular processes of melanocytes out of balance, they can reacquire their old embryonal EMT program. This mechanism might explain why melanoma is such an aggressive cancer type, with a high metastatic capacity. The EMT process might be at the basis of the frequent spreading of melanoma to other organs.
We investigate the transcription factors involved in EMT, mainly ZEB1 and ZEB2. How are these transcription factors influencing tumor initiation? What is their impact on cancer metastasis? Those are the questions we are addressing. We know that ZEB1 is more present in melanocyte stem cells, and in that way its upregulation can contribute to stemness in cancer cells. A lot still needs to be uncovered before we can draw hard conclusions.”
Melanoma check? Easy as ABC
If you are worried about a mole on your arm or a particularly weird spot on your skin, simply apply the ABCs of melanoma. A is for asymmetrical and B is for borders; since the tumor grows in a relatively random fashion, melanomas have irregular edges and shapes. A strongly delineated, perfectly round spot is very unlikely to be a melanoma. C is for color; melanomas are not evenly colored and contain multiple shades of red, brown or black. D represents diameter, as melanomas are usually slightly larger than your average benign mole. Finally, E stands for evolution. If you notice your mole changing in shape, color or size, this might point to risk.
The ABC system provides some basic guidelines, but it is not meant to be a complete diagnostic tool. Always consult your doctor or dermatologist in case of serious concerns or questions.
Dewaele, Michael, et al. "Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth." The Journal of Clinical Investigation 126.1 (2015): 68-84.