PBAF Chromatin Dysfunction May Explain Melanoma's Spread to the Brain

Researchers at the Icahn School of Medicine at Mount Sinai have uncovered a potential mechanism behind the propensity of melanoma, a particularly aggressive skin cancer, to metastasize to the brain. Their recent study, published in the journal Molecular Cell, highlights the critical role of the PBAF chromatin remodeling complex in restraining the expression of certain genes that may facilitate brain invasion.

Chromatin, which constitutes the complex of DNA and proteins forming chromosomes, plays a vital role in regulating gene activity by controlling gene accessibility. The PBAF complex acts as a gatekeeper, orchestrating the organization of chromatin and thus influencing gene activation or suppression. In melanoma tumors, when PBAF function is compromised—a common occurrence—certain neuron-related genes become abnormally expressed in skin cancer cells. These genes seem to enhance the tumor cells' ability to survive and proliferate within the brain environment.

Brain metastasis occurs when cancer cells migrate from their original location to the brain, forming secondary tumors. This process is quite prevalent in melanoma, with estimates indicating that between 40% and 75% of patients with metastatic melanoma develop brain metastases. This is significantly higher than primary brain tumors, which originate within the brain itself.

Lead researcher Dr. Emily Bernstein explained that, unlike the traditional understanding of chromatin remodelers as activators of gene expression, the PBAF complex actually suppresses certain genes in melanoma. When PBAF is damaged, these genes, particularly those linked to neural functions, are turned on, possibly facilitating the cancer’s invasion into the brain. The research team observed that patients harboring PBAF mutations, especially those whose melanoma had metastasized to the brain, exhibited similar gene activation patterns.

This breakthrough suggests promising avenues for improved screening methods and targeted therapies to prevent melanoma spread. By understanding the genetic alterations that promote brain metastasis, clinicians could identify high-risk patients earlier and intervene more effectively. The Mount Sinai team plans to further investigate how these PBAF mutations behave in animal models, focusing on the brain microenvironment, with the goal of developing strategies to halt melanoma progression.

Source: MedicalXpress