One example of malignant melanoma, courtesy of skin cancer foundation

Melanoma: Tel-Aviv University Study Finds Blocking Two Key Proteins May Block Brain Metastases Interview with:
“Prof. Ronit Satchi-Fainaro, the Director of the Cancer Biology Research Center led this study with an outstanding PhD student, Sabina Pozzi”
Prof. Ronit Satchi-Fainaro, Ph.D.
Head, Cancer Research and Nanomedicine Laboratory
Kurt and Herman Lion Chair in Nanosciences and Nanotechnologies
Director, Cancer Biology Research Center
Department of Physiology and Pharmacology
Sackler Faculty of Medicine
Sagol School of Neuroscience
Tel Aviv University, Tel Aviv 69978, Israel What is the background for this study?

Response: Cutaneous melanoma is the deadliest of all skin cancers, especially due to its tendency to invade and develop metastases with an incidence of brain metastasis development of 40% to 50% in patients with melanoma stage IV (although the incidence post mortem is 70–90%).

We know that the brain microenvironment represents the first line of reaction in favor or against the tumor due to its dual ability to generate an immune-stimulatory or immunosuppressive niche, which will ultimately determine the establishment and growth of melanoma brain metastasis. Among the brain-resident cells, astrocytes are responsible for the maintenance of the brain homeostasis, and subsequent to melanoma brain colonization, they sustain and foster the growth of melanoma cells What are the main findings?

Response:  We found that melanoma cells alter astrocytes-secretome, evoke the expression and secretion of an important chemokine, called MCP-1, which in turn induces CCR2 expression in melanoma cells. The result of the interaction between astrocytes and melanoma cells via MCP-1/CCR2 axis enhances the aggressiveness of melanoma cells. Our pharmacological blockade of MCP-1 or molecular knockout using CRISPR/Cas9 of CCR2/CCR4 receptors on melanoma cells delayed the tumor progression of 60-80% in pre-clinical models of melanoma brain metastasis bearing mice. In addition, we were also able to attenuate the immunosuppressive phenotype of the brain microenvironment and improve the activation of the immune cells towards anti-cancer phenotype. What should readers take away from your report?

Response: Development of resistance to chemo- and immuno-therapies often occurs following treatment of melanoma brain metastasis, therefore, the prognosis for patients in advanced stage is still quite poor. We investigated two important proteins involved in the interactions between melanoma cells and astrocytes, and by blocking any of these two proteins, and thus the crosstalk between them, we were able to delay the progression of melanoma metastasis in the brain. What recommendations do you have for future research as a results of this study?

Response: Our pharmacological strategy involved the use of an anti-inflammatory drug that targets MCP-1, Bindarit, currently in clinical trial for non-malignant diseases. In the future, we hope that we will be able to repurpose the use of this drug for melanoma brain metastasis. These findings established valuable foundations for testing the inhibition of this pathway in combination with drugs already approved for the treatment of melanoma brain metastasis.

Response: The new study was funded by the European Research Council (ERC), the Melanoma Research Alliance (MRA), the Kahn Foundation, the Israel Cancer Research Fund (ICRF), and the Israel Science Foundation (ISF).


MCP-1/CCR2 axis inhibition sensitizes the brain microenvironment against melanoma brain metastasis progression

Sabina Pozzi, … , Helena F. Florindo, Ronit Satchi-Fainaro
Published August 18, 2022
Citation Information: JCI Insight. 2022;7(17):e154804

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Last Updated on September 22, 2022 by Marie Benz MD FAAD