Characterizing the functional role of astrogliosis and neuroinflammation in melanoma brain metastasis.

• Applicant: Professor Dr. Tobias Pukrop
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 350030746

The major cause of melanoma mortality is metastasis to distant organs, frequently to the brain. The microenvironment plays a critical role in all stages of tumorigenesis and metastasis. Therefore, in order to cure or prevent metastasis, the interactions of disseminated tumor cells with the microenvironment of the metastatic organ have to be studied. Nevertheless, the role of glial cells in the brain in facilitating metastatic growth is poorly understood. Astrocytes are glial cells that participate in repair and scarring of the brain, and mediate neuroinflammation in response to brain injury. Astrocytes are activated during brain metastasis. However, the role of astrocytes and neuroinflammationin facilitating melanoma brain metastasis is unknown. Using mouse models of spontaneous melanoma brain metastasis, combined with clinical data, organotypic 3D coculture systems and transcriptome profiling, we aim to characterize inflammatory signaling by metastases associated astrocytes. We will elucidate the functional importance of astrogliosis and inflammatory signaling during brain metastasis and determine key regulators within astrocytes that may serve as novel therapeutic targets. Since there are currently no efficient therapies for brain metastasis, it is essential to identify molecular factors that play a role during the early, rate-limiting steps of metastatic colonization of the brain tissue. Achieving control on the astrogliosis response might prove as a novel therapeutic approach to prevent brain metastatic relapse.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professorin Dr. Neta Erez, Ph.D.