LSD1 and BRD9 transcriptome analysis in the MKL-1 Merkel cell carcinoma (MCC) cell line
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PROVIDER: PRJNA514038 | ENA |
REPOSITORIES: ENA
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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: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 | GSE124857 | GEO
Project description:Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine-specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1-CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for proliferation and maintaining cell identity in MCC. There is growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.
2020-11-03 | PXD020590 | Pride
Project description:The overarching goal of this study was to characterize mechanisms of sensitivity to EZH2 inhibitors in Merkel cell carcinoma cell lines. To that end, early and late transcriptional changes were profiled in MKL-1 cells treated with the EZH2 inhibitor EPZ011989 for 6 or 12 days.
2022-03-07 | GSE186896 | GEO
Project description:The overarching goal of this study was to characterize mechanisms of sensitivity to EZH2 inhibitors in Merkel cell carcinoma cell lines. To that end, CUT&RUN for H3K27me3 and H3K4me3 histone marks was performed in MKL-1 cells treated with the EZH2 inhibitor EPZ011989 for 6 days.
2022-03-07 | GSE186897 | GEO
Project description:LSD1 transcriptome analysis in Merkel cell carcinoma (MCC) cell lines
| PRJNA514037 | ENA
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 (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine-specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1-CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for proliferation and maintaining cell identity in MCC. There is growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.
2020-09-04 | GSE147816 | GEO