Investigating Cell of Origin of Merkel Cell Carcinoma, a Historic Misnomer.
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PROVIDER: PRJNA1200673 | ENA |
REPOSITORIES: ENA
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Project description:Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with the poorest prognosis, posited to be derived from Merkel cells. Emerging evidence, however, suggests other potential origins for MCC including hematological lineages. Given the high fatality of MCCs and that many arise in the immune suppressed population, often precluding the use of immunotherapy, it is important to determine the cell of origin for these cancers to elucidate targetable pathways to enable novel treatment approaches. We utilized targeted and multi-omics approaches to explore expression patterns at both the protein and RNA level of MCCs. Western blotting, immunofluorescence, and immunohistochemistry were performed for two patient-derived MCC samples, one MCC cell line, and 92 FFPE samples, respectively, for numerous B-cell markers. Further, RNA sequencing was performed on 17 FFPE patient-derived MCC samples and evaluated by principal component analysis for differentially expressed genes between samples based on sex and MCPyV status. Finally, weighted gene correlation network analysis (WGCNA) and cell type enrichment analyses were employed to determine pathway and cell type enrichment, respectively. MCC patient-derived and cell line samples heterogeneously expressed B-cell and neuroendocrine markers including PAX5, TdT, IgA, CD19, CK20, and chromogranin A. Further, transcriptome analysis demonstrated differentially expressed genes based on sex and MCPyV status. MCPyV+ tumors notably demonstrated significant upregulation of genes involved in immune cell function and downregulation of processes related to neuronal activity. Finally, WGCNA highlighted enrichment for pathways involved in immune function including B-cell differentiation. Cell type enrichment analysis highlighted enrichment for multipotent stem cells, several immune cell types, and keratinocytes. Our findings together with previous results indicate that MCCs are not derived from Merkel cells and instead from multiple or divergent cell types, including those of B-cell lineage. Further, MCC cell of origin may depend on patient and tumour specific characteristics including sex and cell type/differentiation state of a cell infected by the MCPyV. Our work highlights the need for a more personalized approach to diagnosis/characterization and treatment of MCCs given the variability of potentially targetable pathways.
2025-07-01 | GSE284793 | GEO
Project description:Merkel cells are epidermal mechanoreceptor cells responsible for the perception of gentle touch. Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer. Although MCC histologically resembles Merkel cells, the cell of origin for MCC is unknown. MCC frequently contains integrated Merkel cell polyomavirus (MCPyV), a small DNA tumor virus with widespread prevalence. Whether MCPyV can transform Merkel cells is unknown. Here, we describe the isolation and long-term expansion of human Merkel cells from neonatal foreskin. We validated the expression of several Merkel cell-related factors by RNASeq, and assessed the ultrastructure by electron microscopy. Culture of Merkel cell preparations on an artificial basement membrane promoted the formation of structures containing both Merkel and non-Merkel cell populations. To determine whether Merkel cells were susceptible to transformation, we expressed tumor-derived MCPyV T antigens and additional oncogenes. We were unable to demonstrate tumorigenesis in immunodeficient mice, but were able to detect T antigen expression from excised cells weeks after implantation. These results highlight that foreskin-isolated Merkel cells can be propagated extensively, sustain expression of MCPyV T antigens, but are not susceptible to transformation by MCPyV, suggesting that Merkel cells from non-glabrous skin may not be a cell of origin for MCC.
2017-04-01 | GSE79657 | GEO
Project description:Merkel cell carcinoma is supposed to be derived from Merkel cells after infection by Merkel cell polyomavirus (MCV) and other poorly known events. A transcriptional profiling with cDNA microarrays was performed on cells from MCV+ Merkel cell carcinomas and isolated normal Merkel cells. This microarray revealed numerous significantly upregulated genes and down-regulated genes. The extensive list of genes identified in these experiments provides a large body of potentially valuable information of Merkel cell carcinoma carcinogenesis and could represent a source of potential targets for cancer therapy. Two-conditions experiment, MCV vs Normal Merkel Cell. Biological replicates : 4 MCV (Cy5), 1 control = pool of Normal Merkel cells from 3 liftings
2014-01-01 | E-GEOD-50434 | biostudies-arrayexpress
Project description:Merkel cell carcinoma is supposed to be derived from Merkel cells after infection by Merkel cell polyomavirus (MCPyV) and other poorly known events. A transcriptional profiling with cDNA microarrays was performed on cells from MCPyV(+) Merkel cell carcinomas and isolated normal Merkel cells. This microarray revealed numerous significantly upregulated genes and downregulated genes. The extensive list of genes identified in these experiments provides a large body of potentially valuable information of Merkel cell carcinoma carcinogenesis and could represent a source of potential targets for cancer therapy.
2014-01-01 | GSE50434 | GEO
Project description:We performed miRNA expression profiling in a series of human Merkel Cell carcinoma samples using a microarray approach. Significant differentially expressed miRNAs among groups were identified using SAM analysis. Agilent microarray platform containing 723 human miRNAs was used to determine miRNA expression profiles in 16 human Merkel cell carcinoma (MCC) samples. To validate the microarray platform, the expression levels of selected miRNAs were evaluated using qRT-PCR.
2013-12-31 | E-GEOD-43699 | biostudies-arrayexpress
Project description:APOBEC3s mutate Merkel Cell Polyomavirusl genome
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Project description:Array-CGH profiles of Merkel cell carcinoma tumors Experiment Overall Design: We perfromed array-CGH on 25 Merkel cell carcinoma tumor samples (2 primary/metastasis pairs) looking for recurrent gains/losses among the cohort of tumors. Experiment Overall Design: Results from the Analysis of Copy Errors (ACE) may be found in GSE13239_MccACEAnalyzedData.txt. Experiment Overall Design: The overall profiles of the primary/metastasis pairs are similar. These metastases samples, 1m and 3m, were excluded from the ACE analysis.
2009-01-14 | E-GEOD-13239 | biostudies-arrayexpress
Project description:Co-expression of MCPyV TAgs and the Merkel cell lineage determinant ATOH1, in p53-deficient keratinocytes and their neuroendocrine progeny, yields tumors closely mimicking human MCC. Direct cellular reprogramming in vivo may provide a novel approach to generate tumors for which the cell of origin is uncertain.
2022-03-02 | GSE166751 | GEO
Project description:Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin with growing incidence. In research immortalized cell lines are used for in vitro experiments in order to better understand the biology of this malignant disease.
2020-01-09 | PXD008181 | Pride
Project description:Array-CGH profiles of Merkel cell carcinoma tumors Keywords: fresh frozen and formalin fixed paraffin embedded primary tumor, nodal and metastasis merkel cell carcinoma tumor samples
2009-01-01 | GSE13239 | GEO