Correlative study of epigenetic regulation of tumor microenvironment in spindle cell melanomas and cutaneous malignant peripheral nerve sheath tumors

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. Significant histomorphologic challenges frequently arise in the distinction between cutaneous malignant peripheral nerve sheath tumor (C-MPNST) and spindle cell melanoma (SCM) on account that both entities display immunopositivity for S100 and typically do not exhibit immunoreactivity for more specific markers of melanocytic differentiation 1-3. Morphologic infidelity further presents diagnostic hurdles in discriminating between C-MPNSTs and certain amelanotic SCMs, particularly in sun-damaged areas of the skin 2. Rendering the correct diagnosis is crucial as prognosis and patient management are different among these lesions. MPNSTs constitute approximately 3-10% of all soft tissue sarcomas and portend dismal prognosis with propensity for local invasion 4,5. These neoplasms have the proclivity to arise from the deep soft tissues of the upper and lower limbs, and from the trunk 6. C-MPNSTs represent a rare subtype localized to the dermis and/or subcutis with unusual clinical presentation arising primarily in association with neurofibromas 7. The mainstay of

The CTCF/LncRNA‐PACERR complex recruits E1A binding protein p300 to induce pro‐tumour macrophages in pancreatic ductal adenocarcinoma via directly regulating PTGS2 expression

“…Chromatin accessibility regulates cellular transcriptional states by affecting the binding of transcription factors (TFs). To identify the key transcription factors linking the chromatin accessibility with transcriptional characteristics of TAMs, we performed sequence‐based motif analysis with HOMER v4.9 29 and found that the binding sites of CTCF which was a high rank of TFs by motif analysis were significantly enriched in hyper‐accessible regions (Figure 1E) and some previously published articles revealed that CTCF critically controls gene expression in macrophages via epigenetic regulation, 30,31 indicating the upregulation of CTCF activity in TAMs. CTCF was a heritable component of an epigenetic system regulating the interplay between DNA methylation, high chromatin structure, and lineage‐specific gene expression, so we were interested in studying the function of CTCF and locating the key CTCF binding sites in TAMs.…”

Multifunctionality of Calebin A in inflammation, chronic diseases and cancer

“…Altogether, because epigenetic mechanisms are crucial for different clinical outcomes of MPNST patients (129), the results of this study are promising and hold great potential for deeper investigation.…”

MethylBERT: A Transformer-based model for read-level DNA methylation pattern identification and tumour deconvolution

“…Cell-type composition of the tumour microenvironment (TME) consisting of cancer, immune and stromal cells, is crucial for defining clinically relevant tumour subtypes or drug development in immunotherapy [27,28]. DNAm data-based TME deconvolution has been done by using array-based data [29,30] and provided valuable insights in various cancer studies [31,32]. However, sequencing-based TME methylation deconvolution still has not been extensively applied.…”