In a recent study published in Nature Communications, researchers from Moffitt Cancer Center’s Donald A. Adam Melanoma and Skin Cancer Center of Excellence have made significant progress in understanding the mechanisms behind melanoma brain metastasis. Melanoma, the most lethal form of skin cancer, can rapidly spread to the brain, often leading to death within a few months.
The researchers focused their study on identifying the cell signaling pathways that regulate the metastatic spread of melanoma cells to the brain. Melanoma tumors are composed of different subgroups of cells, each with varying abilities to invade surrounding tissues and survive cancer treatments. The researchers wanted to understand how these subgroups contribute to tumor development and progression.
Previous studies conducted by Moffitt researchers revealed that a protein called HDAC8 played a role in regulating resistance to commonly used melanoma treatments. HDAC8 removes chemical modifications known as acetyl groups from other proteins, causing changes in gene expression patterns. Building on this knowledge, the researchers hypothesized that HDAC8 might also be involved in regulating the gene expression patterns of different melanoma subgroups.
Laboratory experiments conducted by the team confirmed that HDAC8 activity increased the survival of melanoma cells under stress conditions, such as low oxygen, UV radiation, and treatment with BRAF/MEK inhibitors. HDAC8 activity also altered the gene expression patterns of the cells, causing them to develop characteristics associated with subgroups capable of migrating and invading surrounding tissues.
Further preclinical experiments revealed that increased HDAC8 expression and activity enhanced the ability of melanoma cells to metastasize specifically to the brain. However, no significant impact was observed in the number of metastatic tumors to other organs, such as the liver or lungs. By studying the molecular pathways of HDAC8-mediated brain metastasis, the researchers discovered that HDAC8 chemically modified a protein called EP300, which subsequently led to the development of invasive characteristics in the cells.
The significance of EP300 to melanoma brain metastasis was confirmed when increased expression of EP300 decreased cell invasion and made melanoma cells more susceptible to cell death. These findings highlight the importance of HDAC8 and EP300 activity in the invasion of melanoma cells to the brain. The researchers believe that targeting these pathways with specific agents may inhibit brain metastasis.
Dr. Keiran Smalley, the lead author of the study and the director of Moffitt’s Melanoma and Skin Cancer Center of Excellence, commented on the significance of the findings. He stated, “Our work provides the first evidence that stress-induced HDAC8 is a regulator of an invasive melanoma cell state that leads to increased brain metastasis.”
Understanding the signaling pathways that govern melanoma brain metastasis is crucial for developing targeted therapies to prevent or treat this deadly form of cancer. The findings of this study provide valuable insights and open up new possibilities for interventions that may improve patient outcomes.
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