Researchers Identify Cell Signaling Pathway Controlling Metastatic Spread of Melanoma Cells to Brain

New research published in Nature Communications discusses the identification a cell signaling pathway that regulates the metastatic spread of melanoma cells to the brain. Melanoma—which is the deadliest form of skin cancer, according to the authors—can grow and spread throughout the body. Over half of individuals with advanced melanoma will experience the disease spreading to the brain, where it progresses quickly and may lead to death in 3 to 4 months.¹

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Melanoma tumors are made up of cell subgroups with different gene expression patterns with different abilities that invade surrounding tissues and survive anti-cancer treatment regimens; however, it is unclear as to how the subgroups contribute to the progression and development of tumors. Previous research determined that the protein histone deacetylase 8 (HDAC8) regulates resistance to BRAF and MEK inhibitors that are commonly used to treat melanoma. HDAC8 can remove chemical modifications called acetyl groups from other proteins, resulting in the alteration of gene expression patterns.¹

The study authors found that HDAC8 activity increased melanoma cell survival under stress conditions (eg, low oxygen, UV radiation, and BRAF/MEK inhibitor treatment). In addition, the researchers also found that HDAC8 activity had changed the gene expression of melanoma cells, causing the cells to develop characteristics that are associated with subgroups that can migrate into and invade surrounding tissues. Further, HDAC8 is unique compared to other class 1 histone deacetylases (HDACs), differing from HDAC1, 2, and 3 in not being phosphorylated and activated by casein kinase 2.^1,2

In addition, the results indicated that an increased HDAC8 expression and activity enhanced the ability of melanoma cells to metastasize to the brain; however, there were no significant impact in the number of metastatic tumors to other organs, such as the liver or lung, observed. HDAC8 was found to chemically modify the protein EP300, which causes cells to develop invasive characteristics. The study authors noted that EP300 is significantly linked to melanoma brain metastases, as an increased expression of EP300 decreases cell invasion, resulting in melanoma cells having a higher sensitivity to cell death.¹

Further, the study authors explained that key steps in the brain’s metastasis were modeled during the study, including the survival of cells in the general circulation, the infiltration of cells into the brain parenchyma, and the establishment of macrometastases. The investigators note that the HDAC8-driven transcriptional state is likely to contribute to several of the processes.²

“These data show the importance of HDAC8 and EP300 activity to melanoma cell invasion to the brain and suggest that agents that target these pathways may inhibit brain metastasis,” said lead study author Keiran Smalley, PhD, director of Moffitt’s Melanoma and Skin Cancer Center of Excellence, in a press release. “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.”¹

References

1. H. Lee Moffitt Cancer Center & Research Institute. Moffitt researchers identify cell signaling pathway controlling melanoma cell metastasis to the brain. News release. November 29, 2023. Accessed December 6, 2023. https://www.eurekalert.org/news-releases/1009516

2. Emmons, MF, Bennett, RL, Riva, A. et al. HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis. Nat Commun. 14, 7759 (2023). doi:10.1038/s41467-023-43519-1