The epigenetic landscape of brain metastasis

Abstract

Brain metastasis represents a significant challenge in oncology, driven by complex molecular and epigenetic mechanisms that distinguish it from primary tumors. While recent research has focused on identifying genomic mutation drivers with potential clinical utility, these strategies have not pinpointed specific genetic mutations responsible for site-specific metastasis to the brain. It is now clear that successful brain colonization by metastatic cancer cells requires intricate interactions with the brain tumor ecosystem and the acquisition of specialized molecular traits that facilitate their adaptation to this highly selective environment. This is best exemplified by widespread transcriptional adaptation during brain metastasis, resulting in aberrant gene programs that promote extravasation, seeding, and colonization of the brain. Increasing evidence suggests that epigenetic mechanisms play a significant role in shaping these pro-brain metastasis traits. This review explores dysregulated chromatin patterns driven by chromatin remodeling, histone modifications, DNA/RNA methylation, and other epigenetic regulators that underpin brain metastatic seeding, initiation, and outgrowth. We provide novel insights into how these epigenetic modifications arise within both the brain metastatic tumor and the surrounding brain metastatic tumor ecosystem. Finally, we discuss how the inherent plasticity and reversibility of the epigenomic landscape in brain metastases may offer new therapeutic opportunities.

Fig. 1. Schematic representing epigenetic mechanisms and their dysregulation in cancer.

Normal regulation of epigenetic mechanisms is essential for physiological cell function. However, alterations in histone post-translational modifications (PTMs), RNA methylation, non-coding RNAs, and DNA methylation have been shown to promote oncogenesis. Histone PTMs alter chromatin accessibility and thus control transcription and DNA binding. In cancer, disruption of this process can lead to chromatin remodeling and aberrant gene expression. RNA methylation controls the fate of mRNA, and exploitation of this process can lead to altered mRNA translation. Non-coding RNAs, including miRNAs, are necessary for the post-transcriptional regulation of mRNA. Dysregulation in their expression or function can lead to unwanted oncogenic mRNA translation. Lastly, DNA methylation, a critical epigenetic mechanism for gene expression control through the addition or removal of methyl groups, can be exploited in cancer-specific contexts to silence tumor suppressors or activate oncogenes. In summary, any imbalance in these processes can result in the transformation of a normal cell into a cancer cell, and loss of control over epigenetic mechanisms can further promote metastatic processes. HAT histone acetyltransferase, HDAC histone deacetylase, HMT histone methyltransferase, HDMT histone demethylase, TF transcription factor, m6A N6-methyladenosine, Me methylation, lncRNA long non-coding RNA, miRNA microRNA, DNMT DNA methyltransferase, TET ten-eleven translocation (enzymes).

Fig. 2. Mutational landscape of epigenetic factors in brain metastatic tumors.

This figure highlights the role of key epigenetic regulators that are frequently mutated in BrM. The data presented are derived from the MSK-MET Tropism Clinical Sequencing Cohort [39, 40], which includes 300 BrM from common primary tumor sources, with a focus on breast (BR), lung (LN), and melanoma (MEL). The data were analyzed using cBioPortal to identify frequently altered epigenetic factors across these tumor types. The figure indicates the mutation rates of these epigenetic regulators for each individual source of BrM. Red colored text indicates epigenetic factors enriched in BrM compared to primary tumors. Asterisks (*) denote statistical significance (p < 0.05) after a two-sided Fisher’s Exact test with Benjamini-Hochberg correction. The diagram also depicts chromatin in both its open and closed states with various key regulators involved. These regulators modulate chromatin accessibility and gene expression by adding, removing, or reading histone marks and DNA methylation patterns. This figure underscores the critical role of epigenetic dysregulation in the pathogenesis of brain metastasis and highlights the potential for targeting these alterations in therapeutic strategies.

Fig. 3. Schematic representing critical epigenetic determinants of key brain metastatic processes.

Brain metastasis is the result of a highly complex series of events, all of which are subject to epigenetic control. Any imbalance in these epigenetic mechanisms can promote brain metastatic processes. CSCs, which initiate metastatic homing, can be driven by the upregulation of genes in the Notch and Hippo pathways through the SWI/SNF complex. Primary tumor-derived EVs, influenced by RNA demethylase FTO, can prime the brain metastatic niche. Contents of these EVs, such as miR-181c, can facilitate degradation of the BBB by downregulating PDPK1 in endothelial cells, allowing metastatic cells to pass into the brain. Once in the brain, metastatic cells interact with their microenvironmental niche. Resident astrocytes can promote cancer cell dormancy by triggering DNMT1 downregulation, which increases the expression of L1CAM and CRYAB while downregulating Wnt signaling. Metastatic cells and reactive glial cells induce transcriptional reprogramming of astrocytes, promoting a more immunosuppressive, pro-tumorigenic microenvironment through the production of IL-10, IFN-α, and BDNF. These pro-tumorigenic astrocytes can further support cancer cell growth through direct junctions with cancer cells, such as connexin 43, leading to the upregulation of MYC and TGLI1, or through astrocyte-secreted molecules like miR-19a, which triggers PTEN loss in cancer cells. Supported by all aspects of the brain microenvironment, metastatic cancer cells can proliferate uncontrollably to form metastases, a process further promoted by epigenetic modulators, EZH2 and HDAC2. Abbreviations: SWI/SNF switch/sucrose non-fermentable, EVs extracellular vesicles, FTO fat mass and obesity-associated protein (RNA demethylase), miR microRNA, PDPK1 3-phosphoinositide-dependent protein kinase-1, DNMT1 DNA methyltransferase 1, L1CAM L1 cell adhesion molecule, CRYAB crystallin alpha B, IL-10 interleukin-10, IFN-α interferon-alpha, BDNF brain-derived neurotrophic factor, EZH2 enhancer of zeste homolog 2, HDAC2 histone deacetylase 2, PTEN phosphatase and tensin homolog.