Epigenetic marks imply a common cellular origin of virus- and UV-associated Merkel cell carcinoma (MCC)
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ABSTRACT:
PROVIDER: PRJNA737485 | ENA |
REPOSITORIES: ENA
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Project description:Differences in DNA-methylation between VP- and UV-MCCs mainly refer to heterogeneity in carcinogenesis rather than an origin in utterly different cell types. Indeed, a principal component derived scoring suggest an epithelial for UV-MCC as well as VP-MCC cell lines.
2022-03-02 | GSE178155 | GEO
Project description:Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin, caused by either excessive UV damage or integration of the Merkel cell polyomavirus (MCV) genome. Here, we report that virally encoded MCV small T antigen (ST) establishes dependence on the LSD1 transcriptional repressor. Inhibition of LSD1 reduces growth of MCV-positive MCC and suppresses ST’s transformation capacity in vitro and in vivo. To define the mechanism of LSD1 inhibition in MCC, we performed a CRISPR loss-of-function library screen. We found that deletion of components of the non-canonical (ncBAF) chromatin remodeler complex confers resistance to LSD1 inhibitors and that LSD1 and ncBAF antagonistically regulate an overlapping set of genes involved in neuron differentiation. Our work provides mechanistic insight into the dependence of MCC on LSD1 and the role of ncBAF as a tumor suppressor in cancer.
2020-02-16 | GSE124857 | GEO
Project description:Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin, caused by either excessive UV damage or integration of the Merkel cell polyomavirus (MCV) genome. Here, we report that virally encoded MCV small T antigen (ST) establishes dependence on the LSD1 transcriptional repressor. Inhibition of LSD1 reduces growth of MCV-positive MCC and suppresses ST’s transformation capacity in vitro and in vivo. To define the mechanism of LSD1 inhibition in MCC, we performed a CRISPR loss-of-function library screen. We found that deletion of components of the non-canonical (ncBAF) chromatin remodeler complex confers resistance to LSD1 inhibitors and that LSD1 and ncBAF antagonistically regulate an overlapping set of genes involved in neuron differentiation. Our work provides mechanistic insight into the dependence of MCC on LSD1 and the role of ncBAF as a tumor suppressor in cancer.
2020-02-16 | GSE124861 | GEO
Project description:When using cell lines to study cancer, phenotypic similarity to the original tumor is paramount. Yet, little has been done to characterize how closely Merkel cell carcinoma (MCC) cell lines model native tumors. To determine their similarity to MCC tumor samples, we characterized MCC cell lines via gene expression microarrays. Using whole transcriptome gene expression signatures and a computational bioinformatic approach, we identified significant differences between variant cell lines (UISO, MCC13, and MCC26) and fresh frozen MCC tumors. Conversely, the classic WaGa and Mkl-1 cell lines more closely represented the global transcriptome of MCC tumors. When compared to publicly available cancer lines, WaGa and Mkl-1 cells were similar to other neuroendocrine tumors, but the variant cell lines were not. WaGa and Mkl-1 cells grown as xenografts in mice had histological and immunophenotypical features consistent with MCC, while UISO xenograft tumors were atypical for MCC. Spectral karyotyping and short tandem repeat analysis of the UISO cells matched the original cell line's description, ruling out contamination. Our results validate the use of transcriptome analysis to assess the cancer cell line representativeness and indicate that UISO, MCC13, and MCC26 cell lines are not representative of MCC tumors, whereas WaGa and Mkl-1 more closely model MCC. RNA was extracted from MCC cell lines and MCC and SCLC tumor samples and hybridized to Affymetrix microarrays for transcriptome profiling.
2014-12-23 | E-GEOD-50451 | biostudies-arrayexpress
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:When using cell lines to study cancer, phenotypic similarity to the original tumor is paramount. Yet, little has been done to characterize how closely Merkel cell carcinoma (MCC) cell lines model native tumors. To determine their similarity to MCC tumor samples, we characterized MCC cell lines via gene expression microarrays. Using whole transcriptome gene expression signatures and a computational bioinformatic approach, we identified significant differences between variant cell lines (UISO, MCC13, and MCC26) and fresh frozen MCC tumors. Conversely, the classic WaGa and Mkl-1 cell lines more closely represented the global transcriptome of MCC tumors. When compared to publicly available cancer lines, WaGa and Mkl-1 cells were similar to other neuroendocrine tumors, but the variant cell lines were not. WaGa and Mkl-1 cells grown as xenografts in mice had histological and immunophenotypical features consistent with MCC, while UISO xenograft tumors were atypical for MCC. Spectral karyotyping and short tandem repeat analysis of the UISO cells matched the original cell line's description, ruling out contamination. Our results validate the use of transcriptome analysis to assess the cancer cell line representativeness and indicate that UISO, MCC13, and MCC26 cell lines are not representative of MCC tumors, whereas WaGa and Mkl-1 more closely model MCC.
2014-12-23 | GSE50451 | GEO
Project description:Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin, caused by either excessive UV damage or integration of the Merkel cell polyomavirus (MCV) genome. Here, we report that virally encoded MCV small T antigen (ST) establishes dependence on the LSD1 transcriptional repressor. Inhibition of LSD1 reduces growth of MCV-positive MCC and suppresses ST’s transformation capacity in vitro and in vivo. To define the mechanism of LSD1 inhibition in MCC, we performed a CRISPR loss-of-function library screen. We found that deletion of components of the non-canonical (ncBAF) chromatin remodeler complex confers resistance to LSD1 inhibitors and that LSD1 and ncBAF antagonistically regulate an overlapping set of genes involved in neuron differentiation. Our work provides mechanistic insight into the dependence of MCC on LSD1 and the role of ncBAF as a tumor suppressor in cancer.
2020-02-16 | GSE140505 | GEO
Project description:Merkel cell carcinoma (MCC), a rare but aggressive neuroendocrine cancer of the skin, remains a challenge in the era of precision medicine. MCC tumor heterogeneity has been attributed to the variant disease etiologies, mediated by either UV exposure or Merkel cell polyomavirus (MCPyV). However, over the years it has become clear that these two groups are largely similar in clinical presentation, prognosis, and treatment response to immune-checkpoint inhibitors. We therefore dissected the transcriptomic heterogeneity of a panel of patient tumors samples, at the single-cell resolution, to gather further insights.
2023-05-22 | GSE226438 | GEO
Project description:MicroRNAs have been implicated in various skin cancers, including melanoma, squamous cell carcinoma, and basal cell carcinoma; however, the expression of microRNAs and their role in Merkel cell carcinoma (MCC) have yet to be explored in depth. To identify microRNAs specific to MCC (MCC-miRs), next-generation sequencing (NGS) of small RNA libraries was performed on different tissue samples including MCCs, other cutaneous tumors, and normal skin. Comparison of the profiles identified several microRNAs upregulated and downregulated in MCC. For validation, their expression was measured via qRT-PCR in a larger group of MCC and in a comparison group of non-MCC cutaneous tumors and normal skin. Eight microRNAs were upregulated in MCC: miR-502-3p, miR-9, miR-7, miR-340, miR-182, miR-190b, miR-873, and miR-183. Three microRNAs were downregulated: miR-3170, miR-125b, and miR-374c. Many of these MCC-miRs, with the miR-183/182/96a cistron in particular, have connections to tumorigenic pathways implicated in MCC pathogenesis. In situ hybridization confirmed that the highly expressed MCC-miR, miR-182, is localized within tumor cells. Furthermore, NGS and qRT-PCR reveals that several of these MCC-miRs are highly expressed in the patient-derived MCC cell line, MS-1. These data indicate that we have identified a set of MCC-miRs with high implications for MCC research. To identify microRNAs specific to Merkel cell carcinoma (MCC) next-generation sequencing (NGS) of small RNA libraries was performed on different tissue samples including MCCs, other cutaneous tumors, and normal skin
2014-03-20 | E-GEOD-53600 | biostudies-arrayexpress
Project description:Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin, caused by either excessive UV damage or integration of the Merkel cell polyomavirus (MCV) genome. Here, we report that virally encoded MCV small T antigen (ST) establishes dependence on the LSD1 transcriptional repressor. Inhibition of LSD1 reduces growth of MCV-positive MCC and suppresses ST’s transformation capacity in vitro and in vivo. To define the mechanism of LSD1 inhibition in MCC, we performed a CRISPR loss-of-function library screen. We found that deletion of components of the non-canonical (ncBAF) chromatin remodeler complex confers resistance to LSD1 inhibitors and that LSD1 and ncBAF antagonistically regulate an overlapping set of genes involved in neuron differentiation. Our work provides mechanistic insight into the dependence of MCC on LSD1 and the role of ncBAF as a tumor suppressor in cancer.
2020-02-16 | GSE124856 | GEO