Zeroing in on drug-tolerant cancer cells

22 September 2018
Single-cell sequencing helps VIB scientists to identify a rare population of stem cell - like melanoma cells 

Identifying new ways to treat cancer is all in a day’s work for Jean-Christophe Marine and his team at the VIB-KU Center for Cancer Biology. In collaboration with research centers in Switzerland and the US, his lab’s most recent research study relied on the power of single-cell sequencing technologies to reveal human melanoma cell behaviors at an unprecedented resolution. The results? Greater insight into dangerous, diverse, melanoma ‘persister’ cells.

Cutaneous melanoma arises from pigment-producing cells (melanocytes) in the skin. When detected early, melanoma can be treated effectively with surgery. More advanced cases of cutaneous melanoma, where cancer cells have spread to other sites in the body, may require treatments such as targeted and immune therapies.

Targeted therapy uses drugs that block specific molecules that are involved in melanoma growth.
A new generation of tablet drugs, called BRAF and MEK inhibitors, have resulted in major improvements in the treatment of patients with advanced melanoma. However, after an impressive initial response, clinical relapse occurs in most patients due to the existence of residual drug-tolerant cell populations.

To better understand how this occurs, the team has focused attention on these residual drug-tolerant cells. They demonstrated that a fraction of cells adapt to the treatment by adopting distinctive features that enables these cells to ‘persist’ despite the presence of the drugs. Specifically targeting these ‘persister’ cells may open new avenues to improve existing treatments.

Group leader Jean-Christophe Marine, postdoc researcher Florian Rambow and PhD student Aljosja Rogiers further explain their research results and highlight the essential role single-cell RNA sequencing played in the identification of these cell populations.

What was the main goal of the project and what new information did it reveal?
Jean-Christophe: “High relapse rates in melanoma indicate that there is something going on that enables a fraction of melanoma cells to survive a treatment that is lethal to most melanoma cells. The goal of our study was to gain a deeper understanding of the biology of these ‘persister’ cells.”

Florian: “The ability of melanoma cells to adapt to the changing environment created by targeted therapy is remarkable and the observation that, within one given melanoma lesion, distinct drug-tolerant cell populations co-emerge upon treatment with targeted therapy, would not have been possible without the power of single-cell RNA sequencing”.

Can these insights potentially be used to target these ‘persister’ cells?
Aljosja: “We have to take into account the immense complexity within and diversity between residual melanoma lesions: “one size fits all” is never going to work. Our attention was drawn to a drug-tolerant cell subpopulation that, in terms of gene expression, displayed stem cell-like features. We could, by specifically targeting this particular cell population, improve the efficacy of a standard treatment in a mouse model. However, one needs to emphasize that much more research is required to enable the translation of these findings into a viable therapeutic approach. Moreover, only targeting that particular cell population may not be sufficient.”

Your team was one of VIB’s early adopters of single-sell sequencing technology. When did the fascination begin?
Jean-Christophe: “We started using scRNAseq back in 2015, initially endorsed by the lab of Thierry Voet at the KU Leuven center for human genetics. The Tech Watch team was also a big help in getting us early access to 10x Genomics, and our collaboration with the Stein Aerts lab (VIB-KU Leuven Center for Brain & Disease Research) was also instrumental in giving us access to top-notch bioinformatics pipelines.

The fact that my lab is part of the LifeTime FET Flagship initiative – a visionary project supporting the use of cutting-edge technology in disease research – is a direct result of our early interest and adoption. Our researchers regularly use single-cell technology and it will absolutely play a central role in our future work.”

What did you expect from this technology in the context of this study?
Jean-Christophe: “Single-cell sequencing allows us to study intra-tumor heterogeneity at a high resolution and will be instrumental in overcoming therapy resistance mechanisms by continuing to identify crucial cell populations – the very populations that would go undetected if it was not for single-cell
RNA sequencing.”

Publication
Rambow et al., Cell 2018


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 Jean-Christophe Marine
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