NVTG-06 MELANOMA BRAIN METASTASES BENEFIT FROM HIGH PRKCZ LEVELS

• Published in: Neuro-oncology advances 2024-08, Vol.6 (Supplement_1), p.i24-i25
• Main Authors: Schöne, Lisa, Meinhardt, Matthias, Mehnert, Marie-Christin, Beissert, Stefan, Meier, Friedegund, Westphal, Dana
• Format: Article
• Language: English
• Subjects: Final Category: Novel Targets in CNS Metastases (Non-Immunologic)
• ISSN: 2632-2498; 2632-2498
• DOI: 10.1093/noajnl/vdae090.080

Abstract Despite current therapies being proven effective against metastasized melanoma, durable responses against melanoma brain metastases remain pending. The main reasons are brain-specific resistance mechanisms, which motivate investigations into the underlying differences between intracranial and extracranial metastases. While the mutational status is mainly unaltered, epigenetic regulation is diverging. Based on methylome and transcriptome analyses of 16 matched intra- and extracranial metastases, 38 protein candidates with distinct promoter methylation and corresponding expression were identified. Eight promising candidates were validated by immunohistochemistry and had a significantly higher protein expression in intracranial metastases. (PMID: 36716920) In this study, we want to investigate the role of a likely cancer-promoting candidate, named protein kinase C zeta (PRKCz), which is upregulated in intracranial metastases. We found a wide range of PRKCz gene expression in various established as well as in-house patient-derived melanoma cell lines. Cell lines with either high or moderate PRKCz expression were chosen for further functional investigation. Using siRNA-mediated knockdown, a decreased viability was seen in PRKCz-knockdown cells in crystal violet assays. To test their role in migration, a 2D wound closure scratch assay was developed and revealed a decreased wound-closure capacity in PRKCz-knockdown cells. Further, PRKCz was found to regulate phosphorylated AKT, a component of the cancer-promoting PI3K/AKT signaling pathway, while phosphorylated ERK, a MAPK signaling component, remained unaffected. In summary, we have shown that PRKCz promotes cell viability and migration in melanoma cells. Melanoma brain metastases therefore benefit from high PRKCz levels in comparison to lower levels in extracranial metastases.