Abstract
The tumor microenvironment (TME) plays critical roles in tumor growth and progression, however key regulators of gene expression in the TME of cutaneous malignant peripheral nerve sheath tumor (C-MPNST) and spindle cell melanoma (SCM) have not been well elucidated. Herein, we investigate the epigenetic regulation of promoters and gene bodies and their effect on the TME composition of C-MPNSTs and SCMs. A cohort of 30 patients was analyzed using differential gene expression (DGE) and gene set enrichment analysis (GSEA) using the Nanostring platform. Methylation analysis was carried out utilizing an Infinium Methylation EPIC array targeting 866,562 methylation site (CpG) islands. DGE revealed overexpression of genes related to mast cells in the TME of SCMs, and a predominance of exhausted CD8+ T cells and macrophages in the TME of C-MPNSTs. Interestingly, we further observed promoter hypermethylation in key overexpressed genes and corresponding gene body hypomethylation. Analysis using ENCODE ChIP-sequencing data identified CTCF as the common transcription factor at the site of the hypomethylated probe. These findings support that the TME composition of C-MPNSTs and SCMs is at least partially independent on promoter methylation status, suggesting a possible relationship between gene body enhancers and expression of key TME genes in both entities.
Highlights
The tumor microenvironment (TME) plays critical roles in tumor growth and progression, key regulators of gene expression in the TME of cutaneous malignant peripheral nerve sheath tumor (C-MPNST) and spindle cell melanoma (SCM) have not been well elucidated
While conventional BRAF and NRAS mutations are not highly prevalent in SCMs, more recently, alterations in genes involved in aberrant activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways have been identified with possibility for targeted therapies with small molecule inhibitors[8]
Our analysis showed strong enrichment in specific genes related to pivotal growth factors (TGFB2, VEGFA), pro-inflammatory cytokines (CXCL5, CXCL6), lysosomal endopeptidases (CTSL), and specific human leukocyte antigen (HLA) alleles (HLA-DQA1, HLA-DQB1) in the C-MPNST group which have been reported to be intricately involved in the pathogenesis of rheumatoid arthritis
Summary
The tumor microenvironment (TME) plays critical roles in tumor growth and progression, key regulators of gene expression in the TME of cutaneous malignant peripheral nerve sheath tumor (C-MPNST) and spindle cell melanoma (SCM) have not been well elucidated. Analysis using ENCODE ChIP-sequencing data identified CTCF as the common transcription factor at the site of the hypomethylated probe These findings support that the TME composition of C-MPNSTs and SCMs is at least partially independent on promoter methylation status, suggesting a possible relationship between gene body enhancers and expression of key TME genes in both entities. The tumor microenvironment (TME) establishes an intricate niche whereby tumor cells interact with neighboring stromal and extracellular matrix elements to create a collaborative setting that promotes tumor progression and an aptitude for metastasis[9,10] Exploration of these entities has provided dynamic insights into the molecular classification and methylome signatures that aid in distinguishing between C-MPNSTs and SCMs, while further laying the foundation for potential future targeted therapies[11,12].
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