Direct cellular reprogramming facilitates development of viral T antigen-driven Merkel cell carcinoma in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE166751 | GEO | 2022/03/02
REPOSITORIES: GEO
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Project description:Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor with high mortality rates. Merkel cell polyomavirus (MCPyV), identified in the majority of MCC, may drive tumorigenesis via viral T antigens. However, mechanisms underlying pathogenesis in MCPyV-negative MCC remain poorly understood. To nominate genes contributing to pathogenesis of MCPyV-negative MCC, we performed DNA microarray analysis on 30 MCCs. MCPyV status of MCCs was determined by PCR for viral DNA and RNA. 1593 probe-sets were differentially expressed between MCPyV-negative and -positive MCC, with significant differential expression defined as at least 2-fold change in either direction and p-value of ≤ 0.05. MCPyV-negative tumors showed decreased RB1 expression, whereas MCPyV-positive tumors were enriched for immune response genes. Validation studies included immunohistochemistry demonstration of decreased RB protein expression in MCPyV-negative tumors and increased peritumoral CD8+ T lymphocytes surrounding MCPyV-positive tumors. In conclusion, our data suggest that loss of RB1 expression may play an important role in tumorigenesis of MCPyV-negative MCC. Functional and clinical validation studies are needed to determine whether this tumor suppressor pathway represents an avenue for targeted therapy. We used microarrays to characterize global gene expression patterns related to Merkel cell polyomavirus status in Merkel cell carcinoma. Furthermore, we compared Merkel cell carcinoma to less aggressive primary cutaneous carcinomas. We utilized flash-frozen tumor tissue from primary Merkel cell carcinomas, metastatic Merkel cell carcinomas, primary cutaneous squamous cell carcinomas, and basal cell carcinomas. Merkel cell carcinoma cell lines, which represent a pure population of tumor cells, were also included. Merkel cell polyomavirus status was determined at the DNA and RNA level using multiple primers for viral T-antigen and capsid protein sequences. This Series represents two analyses - one with new Samples normalized together, and another with some of the new Samples re-normalized with Samples previously submitted under Series GSE13355. The latter group contain 'renormalized' in the titles.
2012-10-18 | E-GEOD-39612 | biostudies-arrayexpress
Project description:Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor with high mortality rates. Merkel cell polyomavirus (MCPyV), identified in the majority of MCC, may drive tumorigenesis via viral T antigens. However, mechanisms underlying pathogenesis in MCPyV-negative MCC remain poorly understood. To nominate genes contributing to pathogenesis of MCPyV-negative MCC, we performed DNA microarray analysis on 30 MCCs. MCPyV status of MCCs was determined by PCR for viral DNA and RNA. 1593 probe-sets were differentially expressed between MCPyV-negative and -positive MCC, with significant differential expression defined as at least 2-fold change in either direction and p-value of ≤ 0.05. MCPyV-negative tumors showed decreased RB1 expression, whereas MCPyV-positive tumors were enriched for immune response genes. Validation studies included immunohistochemistry demonstration of decreased RB protein expression in MCPyV-negative tumors and increased peritumoral CD8+ T lymphocytes surrounding MCPyV-positive tumors. In conclusion, our data suggest that loss of RB1 expression may play an important role in tumorigenesis of MCPyV-negative MCC. Functional and clinical validation studies are needed to determine whether this tumor suppressor pathway represents an avenue for targeted therapy. We used microarrays to characterize global gene expression patterns related to Merkel cell polyomavirus status in Merkel cell carcinoma. Furthermore, we compared Merkel cell carcinoma to less aggressive primary cutaneous carcinomas.
2012-10-18 | GSE39612 | 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 polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1). Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-κB and MYC have been shown to regulate MCT1 expression. While MYC was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-κB subunit RelA, supporting a synergistic activity between MCPyV and MYC in regulating MCT1 levels. Several MCC lines had high levels of MYCL and MYCN but not MYC. Increased levels of MYCL was more effective than MYC or MYCN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis.
2016-10-28 | GSE79968 | 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:Merkel cell polyomavirus (MCPyV) is linked to Merkel cell carcinoma (MCC), a rare and aggressive skin cancer. This study investigated the influence of MCPyV T antigens on the host genome using transcriptomics and epigenomics. Results revealed a role for the small Tumor (sT) antigen in subverting type I interferon response and immune evasion, contributing to persistent infection and tumor progression. These findings enhance our understanding of MCPyV pathogenesis and may inform new therapeutic strategies.
2024-04-04 | GSE230758 | GEO
Project description:Merkel cell polyomavirus (MCPyV) is linked to Merkel cell carcinoma (MCC), a rare and aggressive skin cancer. This study investigated the influence of MCPyV T antigens on the host genome using transcriptomics and epigenomics. Results revealed a role for the small Tumor (sT) antigen in subverting type I interferon response and immune evasion, contributing to persistent infection and tumor progression. These findings enhance our understanding of MCPyV pathogenesis and may inform new therapeutic strategies.
2024-04-04 | GSE229019 | GEO
Project description:Understanding immunotherapy resistance is challenging due to difficulty identifying cancer-specific T cells. Merkel cell carcinoma (MCC) is typically driven by Merkel cell polyomavirus (MCPyV), facilitating identification of cancer-specific T cells across patients. We characterized cancer-specific T cells in 35 MCC patients, including participants in a neoadjuvant anti-PD-1 trial. Higher MCPyV-specific CD8 T-cell frequency in pre-treatment blood (but not tumors) correlated with response (p=0.005). Single-cell transcriptomics revealed MCPyV-specific CD8 T cells in blood had increased stem/memory signatures and decreased exhaustion signatures relative to their intratumoral counterparts. While frequency of peripheral cancer-specific T cells was associated with response to initial PD-(L)1 blockade, longitudinal study of acquired resistance revealed immune evasion by tumor-cell MHC-I downregulation despite cancer-specific T cell expansion to 0.5% in blood. Blood thus appears to be an important reservoir of cancer-specific CD8 T cells and adoptive cell therapies may be particularly effective in patients without such cells.
2023-04-01 | GSE227708 | GEO
Project description:Understanding immunotherapy response and resistance is challenging due to difficulty identifying cancer-specific CD8 T cells. Merkel cell carcinoma (MCC) is typically driven by Merkel cell polyomavirus (MCPyV), facilitating identification of cancer-specific T cells across patients. We characterized cancer-specific T cells in 35 MCC patients, including from a neoadjuvant anti-PD-1 trial. Higher MCPyV-specific CD8 T-cell frequency in pre-treatment blood (but not tumors) correlated with response (p=0.0056). Single cell RNAseq revealed MCPyV-specific CD8 T cells in blood with increased stem/memory signatures and decreased exhaustion signatures relative to their intratumoral counterparts. Number of circulating cancer-specific T cells is likely most linked to primary response to immunotherapy as longitudinal samples documented emergence of additional resistance mechanisms, amidst abundant circulating cancer-specific CD8 T cells. These results suggest that blood acts as an important reservoir of cancer-specific CD8 T cells and suggests adoptive cell therapies may be particularly effective in patients without such cells.
2023-04-01 | GSE227054 | GEO
Project description:Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with neuroendocrine features. Although the role of epigenetic in tumorigenesis has been documented in most type of cancer, it is overlooked in MCC. The treatment options for MCC is limited and the five-year survival rate remains as low as 33%. In addition, recent studies have suggested multiple mechanisms of epigenetic dysregulation that may contribute to loss H3K27me3 and the tumorigenesis in MCC but not well studied. In this study, we conducted DNA methylation analysis of an existing retrospective cohort of clinically annotated MCC samples, which included samples from 8 primary tumors, three metastatic skin tumors, four metastatic lymph node tumors, and five paired normal tissue samples. Global DNA methylation profile was performed using Illumina Infinium MethylationEPIC array. Two MCC cell lines were also analyzed for DNA methylation and gene expression (RNA-seq) to confirm the correlation between DNA methylation and gene expression for MCC. Our analysis revealed 24,497 loci (14,456 genes) that showed significantly different DNA methylation pattern in the four groups (ANOVA p-value < 0.05 and standard deviation of mean of groups > 0.25) namely adjacent normal, primary tumor, metastatic skin, and metastatic lymph node in MCC patients. By GO terms analysis, the genes correlated with DNA methylation alteration associated with nervous system, cell adhesion, signal transduction, and development pathways. We also observed 870 probes differentially methylated in MCPyV positive and MCPyV negative tumor (FDR adjusted p-value < 0.05 and delta change greater than 0.4 or less than -0.4). Furthermore, using expression and DNA methylation data from two MCC cell lines (MS1 and MCC13) as validation, we identified 964 MCC specific genes directly regulated by DNA methylation either at promoter or gene body, which are highly enriched in nervous system related pathways. By this approach, we not only identify DNA methylation markers for MCC and MCPyV status but also genes regulated by DNA methylation in MCC, MCPyV status, and neuroendocrine features. Most importantly, our results may also suggest overexpression of KDM6B and EZHIP by loss of DNA methylation in their promoter may contribute to loss of H3K27me3 in MCC. In addition, we observed the DNA methylation profile of MS1 resembled MCC patient sample, while DNA methylation profile of MCC13 cell line was similar to small cell lung carcinoma (SCLC), which suggested that MCC13 cell line may originally come from SCLC. Taken together, we have demonstrated dramatic DNA methylation alteration along with four unique patterns in normal, primary and metastatic MCC. Our finding provides DNA methylation markers not only for diagnosis or prognosis of MCC and MCPyV status but also correlate gene expression status of MCC specific genes with important functional roles in MCC tumorigenesis, MCPyV expression, neuroendocrine feature and H3K27me3 status. The identification of DNA methylation alteration in MCC also provides foundation for potential implication of epigenetic therapy for MCC patients.
2021-07-13 | GSE160878 | GEO