When it comes to finding a cure for melanoma skin cancer, major strides are being taken as we speak. One of the driving forces behind this great work is Chris Marine (VIB/KU Leuven). His team has recently achieved two important breakthroughs in melanoma research. Let’s take a closer look at their remarkable endeavors.
The first study involved an international collaboration with researchers from Singapore. Published in the leading Journal of Clinical Investigation, it suggested a new way of interfering with the mechanism by which melanoma prevent natural tumor suppressors from doing their work. Chris and his PhD student Karen Willekens elaborate on their findings.
Why is this study so important, Chris?
Chris: “As everybody knows, the ultimate goal of cancer cells is to multiply. But there is a specific protein, called p53, that suppresses this multiplication. In the case of melanoma, however, cancer cells manage to inactivate p53 by overexpressing MDM4, another protein. Previous research from my lab focused on targeting the physical interaction between MDM4 and p53, which proved to be a real struggle. Instead, we have now discovered a method allowing the targeting of MDM4 abundance. It’s an important finding, because this method showed great therapeutic potential in mouse models and, importantly, is amenable to the clinic.”
Karen, which lesson learned will help you in future research?
Karen: “Always be prepared for the unexpected! In this case, all of our initial hypotheses turned out to be wrong. We had to accept our negative results and adapt to our unexpected findings, trust these “strange” results and keep moving forward, following logic reasoning. It all made sense in the end, but it was still a surprising and exciting result.”
Chris, the paper described a SAMMSON ‘addiction’. Can you explain?
Chris: “Expressed in more than 90% of malignant – and not in benign – human melanomas, this lncRNA is paramount to the survival of melanoma cells. In both in vitro and pre- clinical studies in mice, the reduction of SAMMSON through targeted antisense molecules makes cancer cells rapidly and massively die off. We also discovered that this lncRNA is recruited to mitochondria, an organelle that provides energy to the cancer cells. By promoting the degradation of SAMMSON, these antisense molecules disrupt vital mitochondrial activity, which stops the tumor’s growth.”
Non-coding RNAs – long considered ‘junk DNA’ – are emerging as potentially important molecules in various biological processes and diseases. Together with postdoctoral scientist Eleonora Leucci and researchers from the University of Ghent, Chris discovered a new long non-coding RNA (lncRNA) gene called SAMMSON, which is crucial for melanoma survival. The importance of this discovery to the development of both diagnostic and therapeutic tools was illustrated in the March issue of Nature.
Eleonora, congratulations with the Nature publication! Did you celebrate it?
Eleonora: “A Nature paper is such an intense experience that the only appropriate celebration would be one month off on a tropical island. But I’m already working on the next study, so no special celebrations for me. We did have a few drinks with our colleagues, however.”
How did the publication affect your next steps in this research?
Eleonora: “SAMMSON increased the visibility of our laboratory in the non-coding RNA and melanoma field, leading to new and interesting collaborations with top scientists in the future. I see the paper as an essential starting point, but there are still many scientific questions to be answered. Moreover I already received enthusiastic messages from patients and their relatives, encouraging us to proceed with our studies. Perhaps after the publication I feel more responsible towards these people and motivated to bring SAMMSON to the next level.”
Are you already teaming up with industrial partners?
Eleonora: “We are currently looking for partners who want to invest in our project. In the meantime, we are also collaborating with companies to develop more potent SAMMSON inhibitors and to perform toxicological studies. When all this work is done, we will finally be able to contact clinicians to start a trial. All these steps require communication and persuasion skills, which are not obvious for a scientist! But luckily, we are not alone in this venture: VIB has an excellent tech transfer team.”
Dewaele et al., Journal of Clinical Investigation 2015
Leucci et al., Nature 2016
(Article from VIB)