12.03.2024: Malignant melanoma - also known as "black skin cancer" - is the most malignant form of skin cancer. One of the reasons why it is so dangerous is that up to 40% of all melanoma patients develop brain metastases in the course of the disease. This is a serious obstacle to successful treatment. Now a breakthrough in the fight against this metastasis may have been achieved: an research team led by Torben Redmer (University of Veterinary Medicine Vienna) and Josefine Radke (University Medical Centre Greifswald) identified the MET receptor as a promising new target for future therapies of melanoma-associated brain metastases.

The development of primary and secondary brain tumors is strongly determined by the interaction of tumor cells and cells from the tumor microenvironment - in particular stromal cells of the brain such as astrocytes, microglia and infiltrated macrophages - and the resulting activation of inflammatory processes. Although the neuroinflammatory processes associated with the development and progression of primary brain tumors such as glioblastoma have been intensively researched, numerous mechanisms that accompany the development of brain metastases have been little studied.

Crucial for the discovery of new therapeutic strategies

In their recently published study, the scientists combined transcriptome and methylome analyses to decipher the molecular characteristics of melanoma brain metastases (MBM) at different stages of progression, which exhibit high or low infiltration of tumor-associated macrophages and microglial cells (TAMs) regardless of phenotype (Ecad, NGFR). First author Torben Redmer from the Institute of Medical Biochemistry and Pathology at the Vetmeduni explains why this is of great relevance: "Understanding the processes involved in the development and maintenance of melanoma brain metastases is crucial for the discovery of new therapeutic strategies."

New prognostic markers for favourable disease progression

Through pathological and in vivo examinations, the researchers were able to identify potential prognostic markers for a favourable disease course and response to therapy with immune checkpoint inhibitors (ICi), including APBB1IP and the interferon-responsive gene ITGB7. "In MBM with high ITGB7/APBB1IP levels, the accumulation of TAMs correlated significantly with the immune score, predicting a better prognosis for melanoma patients. The activation of the MET receptor is possibly triggered by inflammatory processes in disseminating melanoma cells of the brain via the hepatocyte growth factor HGF released by stromal cells," says Josefine Radke, the study's last author.

MET gene as a new therapeutic target

Since the activation of the MET receptor in melanoma cells that colonise the brain promotes the self-preservation and expansion of the tumor and could counteract the success of ICi therapy, Torben Redmer and Josefine Radke believe that this provides a new starting point: "Therapeutic targeting of MET may be a promising strategy for controlling brain metastasis and improving patient survival."

The article „MET receptor serves as a promising target in melanoma brain metastases“ by Torben Redmer, Elisa Schumann, Kristin Peters, Martin E. Weidemeier, Stephan Nowak, Henry W. S. Schroeder, Anna Vidal, Helena Radbruch, Annika Lehmann, Susanne Kreuzer‑Redmer, Karsten Jürchott and Josefine Radke was published in „Acta Neuropathologica“.

Scientific article