Preclinical characterisation and development of a novel myelodysplastic syndrome-derived cell line.
Ontology highlight
ABSTRACT:
SUBMITTER: Shafiee S
PROVIDER: S-EPMC8112349 | biostudies-literature | 2021 Apr
REPOSITORIES: biostudies-literature
Publications
Preclinical characterisation and development of a novel myelodysplastic syndrome-derived cell line.
Shafiee Sahba S Gelebart Pascal P Popa Mihaela M Hellesøy Monica M Hovland Randi R Brendsdal Forthun Rakel R Lee Jungwoo J Tohyama Kaoru K Molven Anders A Parekkadan Biju B Tore Gjertsen Bjørn B Olsnes Kittang Astrid A McCormack Emmet E
British journal of haematology 20210309 2
Similar Datasets
Project description:Patients with Myelodysplastic syndromes (MDS) have few therapy options for sustainable responses in the frontline setting, and even less after hypomethylating agent (HMA) failure in relapsed and refractory setting. The only potential cure is an allogeneic hematopoietic stem cell transplant which is an unrealistic option for the majority of MDS patients. Immunotherapy with checkpoint inhibition, CAR-T cells, and vaccine therapy few have shown promise in a variety cancer and have now been tested in patients with MDS. Most trials have focused on AML patients and included small numbers of MDS patients. Until now, a dedicated review of immunotherapy outcomes in MDS patients has been lacking. Thus, herein we review outcomes of MDS patients after immunotherapies on a variety of clinical trials reported to date.
| S-EPMC8475606 | biostudies-literature
Project description:Aberrant activation of the transcription factor NF-κB, as well as uncontrolled inflammation, has been linked to autoimmune diseases, development and progression of cancer, and neurological disorders like Alzheimer's disease. Reporter cell lines are a valuable state-of-the art tool for comparative analysis of in vitro drug screening. However, a reporter cell line for the investigation of NF-κB-driven neuroinflammation has not been available. Thus, we developed a stable neural NF-κB-reporter cell line to assess the potency of proinflammatory molecules and peptides, as well as anti-inflammatory pharmaceuticals. We used lentivirus to transduce the glioma cell line U251-MG with a tandem NF-κB reporter construct containing GFP and firefly luciferase allowing an assessment of NF-κB activity via fluorescence microscopy, flow cytometry, and luminometry. We observed a robust activation of NF-κB after exposure of the reporter cell line to tumour necrosis factor alpha (TNFα) and amyloid-β peptide [1-42] as well as to LPS derived from Salmonella minnesota and Escherichia coli. Finally, we demonstrate that the U251-NF-κB-GFP-Luc reporter cells can be used for assessing the anti-inflammatory potential of pharmaceutical compounds using Bay11-7082 and IMD0354. In summary, our newly generated cell line is a robust and cost-efficient tool to study pro- and anti-inflammatory potential of drugs and biologics in neural cells.
| S-EPMC5534271 | biostudies-other
Project description:Synovial sarcoma is a rare translocation-driven cancer with poor survival outcomes, particularly in the advanced setting. Previous synovial sarcoma preclinical studies have relied on a small panel of cell lines which suffer from the limitation of genomic and phenotypic drift as a result of being grown in culture for decades. Patient-derived xenografts (PDX) are a valuable tool for preclinical research as they retain many histopathological features of their originating human tumour; however, this approach is expensive, slow, and resource intensive, which hinders their utility in large-scale functional genomic and drug screens. To address some of these limitations, in this study, we have established and characterised a novel synovial sarcoma cell line, ICR-SS-1, which is derived from a PDX model and is amenable to high-throughput drug screens. We show that ICR-SS-1 grows readily in culture, retains the pathognomonic SS18::SSX1 fusion gene, and recapitulates the molecular features of human synovial sarcoma tumours as shown by proteomic profiling. Comparative analysis of drug response profiles with two other established synovial sarcoma cell lines (SYO-1 and HS-SY-II) finds that ICR-SS-1 harbours intrinsic resistance to doxorubicin and is sensitive to targeted inhibition of several oncogenic pathways including the PI3K-mTOR pathway. Collectively, our studies show that the ICR-SS-1 cell line model may be a valuable preclinical tool for studying the biology of anthracycline-resistant synovial sarcoma and identifying new salvage therapies following failure of doxorubicin.
| S-EPMC9368503 | biostudies-literature
Project description:BackgroundCell lines provide a powerful model to study cancer and here we describe a new spontaneously immortalised epithelial ovarian cancer cell line (NUOC-1) derived from the ascites collected at a time of primary debulking surgery for a mixed endometrioid / clear cell / High Grade Serous (HGS) histology.ResultsThis spontaneously immortalised cell line was found to maintain morphology and epithelial markers throughout long-term culture. NUOC-1 cells grow as an adherent monolayer with a doubling time of 58 hours. The cells are TP53 wildtype, positive for PTEN, HER2 and HER3 expression but negative for oestrogen, progesterone and androgen receptor expression. NUOC-1 cells are competent in homologous recombination and non-homologous end joining, but base excision repair defective. Karyotype analysis demonstrated a complex tetraploid karyotype. SNP array analysis of parent and derived subpopulations (NUOC-1-A1 and NUOC-1-A2) cells demonstrated heterogeneous cell populations with numerous copy number alterations and a pro-amplification phenotype. The characteristics of this new cell line lends it to be an excellent model for investigation of a number of the identified targets.Materials and methodsThe cell line has been characterised for growth, drug sensitivity, expression of common ovarian markers and mutations, clonogenic potential and ability to form xenografts in SCID mice. Copy number changes and clonal evolution were assessed by SNP arrays.
| S-EPMC5432300 | biostudies-literature
Project description:BackgroundMast cell tumour (MCT) is a life-threatening neoplasm commonly found in dogs worldwide. The outcome of treatment for dogs with cutaneous MCT is currently poor, mainly because of the tumour's aggressiveness and the heterogeneity in tumour behaviour. This study established a novel canine MCT cell line and compared with three reference canine MCT cell lines (CMMC, VIMC and CoMS) in terms of their characteristics and tumour sensitivity to immune cell-mediated cytotoxicity.ResultsOf 18 MCT samples, only one cell line derived from high grade cutaneous MCT was established and referred to as C18 cell line. The C18 cell line could be maintained for over 100 passages while they still exhibited c-kit, tryptase, FcεRIα and FcεRIβ expression. The C18 had the longest doubling time and smallest tumour spheroid size when compared to the other three reference cell lines. The C18 also had c-kit internal tandem duplication (ITD) in exon 11 and nine single nucleotide polymorphisms (SNPs) in five genes, namely c-kit, HYAL4, SEL1L, SPAM1 and TRAF3. For a comparison of tumour sensitivity to immune cell-mediated cytotoxicity, the percentages of early and total apoptotic cells were significantly increased in all four cell lines. However, the percentages of viable cells were significantly decreased only in C18.ConclusionIn conclusion, a novel canine cutaneous MCT cell line was successfully established, in terms of its characteristics, growth behavior and interaction with PBMCs. The C18 cell line holds a potential promise for advancing studies and developing new therapeutic strategies.
| S-EPMC11884003 | biostudies-literature
Project description:Current treatment of paediatric hepatocellular carcinoma (HCC) is often inefficient due to advanced disease at diagnosis and resistance to common drugs. The aim of this study was to generate a cell line derived from a paediatric HCC in order to expand research in this field. We established the HC-AFW1 cell line from a liver neoplasm of a 4-year-old boy through culturing of primary tumor specimens. The cell line has been stable for over one year of culturing and has a doubling time of 40 h. The tumour cells have an epithelial histology and express HCC-associated proteins such as Alpha-fetoprotein (AFP), Glypican 3, E-cadherin, CD10, CD326, HepPar1 and Vimentin. Forty-nine amino acids in exon 3 of β-Catenin that involve the phosphorylation sites of GSK3 were absent and β-Catenin is detectable in the cell nuclei. Cytogenetic analysis revealed large anomalies in the chromosomal map. Several alterations of gene copy numbers were detected by genome-wide SNP array. Among the different drugs tested, cisplatin and irinotecan showed effective inhibition of tumour cell growth in a proliferation assay at concentrations below 5 µg/ml. Subcutaneous xenotransplantation of HC-AFW1 cells into NOD/SCID mice resulted in fast growing dedifferentiated tumours with high levels of serum AFP. Histological analyses of the primary tumour and xenografts included national and international expert pathological review. Consensus reading characterised the primary tumour and the HC-AFW1-derived tumours as HCC. HC-AFW1 is the first cell line derived from a paediatric HCC without a background of viral hepatitis or cirrhosis and represents a valuable tool for investigating the biology of and therapeutic strategies for childhood HCC.
| S-EPMC3364222 | biostudies-literature
Project description:Testicular cancer (TC) is the most common solid tumour in young men. While cisplatin-based chemotherapy is highly effective in TC patients, chemoresistance still accounts for 10% of disease-related deaths. Pre-clinical models that faithfully reflect patient tumours are needed to assist in target discovery and drug development. Tumour pieces from eight TC patients were subcutaneously implanted in NOD scid gamma (NSG) mice. Three patient-derived xenograft (PDX) models of TC, including one chemoresistant model, were established containing yolk sac tumour and teratoma components. PDX models and corresponding patient tumours were characterised by H&E, Ki-67 and cyclophilin A immunohistochemistry, showing retention of histological subtypes over several passages. Whole-exome sequencing, copy number variation analysis and RNA-sequencing was performed on these TP53 wild type PDX tumours to assess the effects of passaging, showing high concordance of molecular features between passages. Cisplatin sensitivity of PDX models corresponded with patients' response to cisplatin-based chemotherapy. MDM2 and mTORC1/2 targeted drugs showed efficacy in the cisplatin sensitive PDX models. In conclusion, we describe three PDX models faithfully reflecting chemosensitivity of TC patients. These models can be used for mechanistic studies and pre-clinical validation of novel therapeutic strategies in testicular cancer.
| S-EPMC7641131 | biostudies-literature
Project description:The epigenetic silencing of tumor suppressor genes in myelodysplastic syndromes (MDS) can potentially confer a growth advantage to individual cellular clones. Currently, the recommended treatment for patients with high-risk MDS is the methylation agent decitabine (DAC), a drug that can induce the reexpression of silenced tumor suppressor genes. We investigated the effects of DAC treatment on the myeloid MDS cell line SKM-1 and investigated the role of FOXO3A, a potentially tumor-suppressive transcription factor, by silencing its expression prior to DAC treatment. We found that FOXO3A exists in an inactive, hyperphosphorylated form in SKM-1 cells, but that DAC both induces FOXO3A expression and reactivates the protein by reducing its phosphorylation level. Furthermore, we show that this FOXO3A activation is responsible for the DAC-induced differentiation of SKM-1 cells into monocytes, as well as for SKM-1 cell cycle arrest, apoptosis, and autophagy. Collectively, these results suggest that FOXO3A reactivation may contribute to the therapeutic effects of DAC in MDS.
| S-EPMC5662805 | biostudies-literature
Project description:BackgroundSomatic mutations are widespread in patients with Myelodysplastic Syndrome (MDS) and are associated with prognosis. However, a practical prognostic model for MDS that incorporates somatic mutations urgently needs to be developed.MethodsA cohort of 201 MDS patients from the Gene Expression Omnibus (GEO) database was used to develop the model, and a single-center cohort of 115 MDS cohorts from Northwest China was used for external validation. Kaplan-Meier analysis was performed to compare the effects of karyotype classifications and gene mutations on the prognosis of MDS patients. Univariate and multivariate Cox regression analyses and Lasso regression were used to screen for key prognostic factors. The shinyapps website was used to create dynamic nomograms with multiple variables. The time-dependent receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA) were used to evaluate the model's discrimination, accuracy and clinical utility.ResultsSix risk factors (age, bone morrow blast percentage, ETV6, TP53, EZH2, and ASXL1) were considered as predictor variables in the nomogram. The nomogram showed excellent discrimination, with respective the area under the ROC curve (AUC) values of 0.850, 0.839, 0.933 for the training cohort at 1 year, 3 years and 5 years; 0.715, 0.802 and 0.750 for the testing cohort at 1 year, 3 years and 5 years; and 0.668, 0.646 and 0.731 for the external validation cohort at 1 year, 3 years and 5 years. The calibration curves and decision curve showed that the nomogram had good consistency and clinical practical benefit. Finally, a stratified analysis showed that MDS patients with high risk had worse survival outcomes than patients with low risk.ConclusionWe developed a nomogram containing six risk factors, which provides reliable and objective predictions of prognosis for MDS patients.
| S-EPMC9597308 | biostudies-literature
Project description:Although paediatric high grade gliomas resemble their adult counterparts in many ways, there appear to be distinct clinical and biological differences. One important factor hampering the development of new targeted therapies is the relative lack of cell lines derived from childhood glioma patients, as it is unclear whether the well-established adult lines commonly used are representative of the underlying molecular genetics of childhood tumours. We have carried out a detailed molecular and phenotypic characterisation of a series of paediatric high grade glioma cell lines in comparison to routinely used adult lines.All lines proliferate as adherent monolayers and express glial markers. Copy number profiling revealed complex genomes including amplification and deletions of genes known to be pivotal in core glioblastoma signalling pathways. Expression profiling identified 93 differentially expressed genes which were able to distinguish between the adult and paediatric high grade cell lines, including a number of kinases and co-ordinated sets of genes associated with DNA integrity and the immune response.These data demonstrate that glioma cell lines derived from paediatric patients show key molecular differences to those from adults, some of which are well known, whilst others may provide novel targets for evaluation in primary tumours. We thus provide the rationale and demonstrate the practicability of using paediatric glioma cell lines for preclinical and mechanistic studies.
| S-EPMC2666263 | biostudies-literature