A team of scientists from Belgium, Switzerland and the United States led by Jean-Christophe Marine (VIB-KU Leuven Center for Cancer Biology) has demonstrated that melanoma cells are capable of adapting their behavior when exposed to therapy to become highly resilient. The team identified one subpopulation of ‘persistent’ cancer cells that can lead to therapy failure, as they provide a pool of cells from which cancer eventually regrows. Their research results will be published in the leading academic journal Cell

Cutaneous melanoma arises from pigment-producing cells (melanocytes) in the skin. When detected early, melanoma can be effectively treated by surgical excision. More advanced cases of cutaneous melanoma, where cancer cells have spread to other sites throughout 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.

Researchers used single-cell sequencing technologies to study, for the first time, the biology of these residual drug-tolerant cell populations.

Single-sell sequencing highlights the diversity of cancer ‘persisters’ 
The team’s results reveal that cancer cells are very creative in finding escape strategies to avoid otherwise effective therapies. As a result, cancer treatments that destroy most of a tumor cause, in the meantime, certain cells to become even more resistant to therapy.

Dr. Jean-Christophe Marine (VIB-KU Leuven): “While many melanoma cells are eliminated under therapeutic pressure, other cells switch on diverse survival programs and adopt distinct behaviors to avoid being killed. Our research indicates that these ‘persister’ cells, which maintain a minimal residual cancer presence even after treatment, are surprisingly diverse.”

“The use of single-cell sequencing technologies allowed us to identify one key subpopulation of ‘persister’ cells. We observed that among all subpopulations of ‘persister’ cells, one of them shares many traits with cancer stem cells.”

Challenging classical approaches to cancer treatment 
The team’s overarching goal for the project was to gain deeper understanding of ‘persister’ cell biology in order to determine potential therapeutic strategies to target them and prevent melanoma relapse.

Dr. Jean-Christophe Marine (VIB-KU Leuven): “Discovering that these minimal residual disease lesions are so heterogeneous and thus difficult to target was unexpected, and initially a serious concern for us. However, the identification of the main driver behind this key subpopulation helped us finding a pharmacological method to target this particular cell population. With this approach, we could improve the efficacy of a standard treatment in a melanoma mouse model.”

“Although our findings support the observation that cancer therapies actually increase tumor complexity by causing ‘persister’ cells to engage diverse survival mechanisms, a better understanding of the drug-tolerant landscape offered us the possibility of targeting one key cancer cell population before relapse becomes evident. This challenges the classical principle in cancer therapy in which the start of a new treatment is postponed until clinical relapse occurs.”

Future steps in this research include expanding preclinical evidence for this approach in other models of melanoma and eventually transferring this knowledge into clinical benefit for patients.

Publication
Toward minimal residual disease-directed therapy in melanoma,  Rambow et al. Cell, August, 2018

Questions from patients
A breakthrough in research is not the same as a breakthrough in medicine. The realizations of VIB researchers can form the basis of new therapies, but the development path still takes years. This can raise a lot of questions. That is why we ask you to please refer questions in your report or article to the email address that VIB makes available for this purpose: [email protected] Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.

 

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