Melanoma research accelerates with two new VIB breakthroughs

29 December 2017
​The researchers of the Jean-Christophe Marine lab (VIB-KU Leuven Center for Cancer Biology) are continuously hard at work investigating cancer pathways – focusing particularly on melanoma. Their results have been nothing short of transformative, with two recent papers revealing key insights into the development of – and potential targeted therapies for – melanoma tumors.

Published in Cell Stem Cell and Nature Cell Biology the two collaborative papers are co-authored by (among
others) Jean-Christophe Marine, PhD student Corinna Kohler, Staff Scientist David Nittner and postdoc scientist Florian Rambow. They’re eager to give us the story behind their discoveries.

Jean-Christophe and Corinna, can you share a little bit about your paper?
Corinna: “We used a mouse model that recreates the early stages of melanoma development in humans. We observed mature melanocytes, or pigmentproducing cells in the top layer of the skin, expanding, changing their appearance and then losing their normal ‘melanocyte’ characteristics before becoming malignant cancer cells. This was in direct contrast with the activities of other types of skin cells, such as nonpigmented or stem-like melanocytes.”

What surprised you about these observations?
Jean-Christophe: “This data clearly shows that mature, differentiated cells can serve as the cellular origin of a tumor. This contrasts with most – if not all – other in vivo tumor lineage tracing studies to date showing that stem or progenitor cells are cells of origin – such as in intestinal adenoma and basal cell carcinoma.”

Did you use any special techniques or technologies?
Corinna: “The up-and-coming single-cell RNA sequencing technique was an essential part of our study, as was in vivo time lapse imaging allowing us to monitor both morphological and molecular changes in melanoma-initiating cells from the moment they entered their very first cell division onwards. We were the first to combine these powerful techniques with in vivo lineage tracing approaches to study the very first steps of tumor initiation and development in vivo.”

Jean-Christophe: “These mouse models set our study apart. By inducing cancer specifically on the tail skin
of our mice, we developed a refined model that faithfully mimics key features of the human disease."

Florian and Jean-Christophe, your paper in Nature Cell Biology also yielded impactful results. Tell us more?
Florian: “We collaborated with the research group of Marie-Dominique Galibert at IGDR (Institut de
Génétique & Développement de Rennes, France), discovering a new role for the protein-coding gene TYRP1. This gene is known to be involved in the production of pigment, but can also promote tumor growth in melanoma.”

Did you find anything surprising about this discovery?
Florian: “What was most intriguing is that TYRP1 only promotes tumor growth through a nonprotein coding function. A portion of the TYRP1 gene acts as a sponge, soaking up RNA molecules that fight tumors and making the environment more favorable to tumor growth.”

Jean-Christophe: “Interestingly, we can use this observation to develop new therapeutics that block TYRP1’s ‘RNA-sponge’ effect, restoring the RNA’s potent antimelanoma activity. We demonstrated this possibility in our study using a well-accepted preclinical patient-derived xenograft (PDX) model.”

How soon do you think we will see practical applications of this research?
Jean-Christophe: “The field of melanoma research is going through an exciting period, with more than 300 ongoing clinical trials. Targeted immunotherapy has made great strides in the last five years. However, resistance mechanisms that melanoma cells use to fight current treatment strategies remain important obstacles to overcome. The difficulties in treating melanoma stem from its very diverse tumor types and the plasticity of melanoma tumor cells. Single-cell genomics is emerging as a powerful tool for the study of individual cancer cells in high detail. This combined with our clearer understanding of the non-coding genome, we’re closer than ever to thoroughly mapping melanoma dependencies and vulnerabilities.”

“In other words: melanoma research is currently on a steep learning curve – we’re gathering key information that will vastly improve the clinical management of melanoma patients.”

Publication
Kohler, Nittner et al., Cell Stem Cell 2017
Gidot, Migault et al., Nature Cell Biology 2017


Jean-Christophe Marine, David Nittner, Corinna Köhler and Florian Rambow