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Expression of FUS-CHOP fusion protein in immortalized/transformed human Mesenchymal Stem Cells drives mixoid liposarcoma formation

ABSTRACT: Although different sarcomas have been modeled in mice upon expression of fusion oncogenes in MSCs, sarcomagenesis has not been successfully modeled in human MSCs (hMSCs). We report that FUS-CHOP, a hallmark fusion gene in mixoid liposarcoma (MLS), has an instructive role in lineage commitment, and its expression in hMSC sequentially immortalized/transformed with up to 5 oncogenic hits (p53 and Rb deficiency, hTERT over-expression, c-myc stabilization and H-RASv12 mutation) drives the formation of serially transplantable MLS. This is the first model of sarcoma based on the expression of a sarcoma-associated fusion protein in hMSC, and allowed us to unravel the differentiation processes and signaling pathways altered in the MLS-initiating cells. This study will contribute to test novel therapeutic approaches, and constitutes a proof-of-concept to employ hMSCs as target cell for modeling other fusion gene-associated human sarcomas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48030 | GEO | 2013/06/18

SECONDARY ACCESSION(S): PRJNA208727

REPOSITORIES: GEO

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Expression of FUS-CHOP fusion protein in immortalized/transformed human Mesenchymal Stem Cells drives mixoid liposarcoma formation

Project description:Although different sarcomas have been modeled in mice upon expression of fusion oncogenes in MSCs, sarcomagenesis has not been successfully modeled in human MSCs (hMSCs). We report that FUS-CHOP, a hallmark fusion gene in mixoid liposarcoma (MLS), has an instructive role in lineage commitment, and its expression in hMSC sequentially immortalized/transformed with up to 5 oncogenic hits (p53 and Rb deficiency, hTERT over-expression, c-myc stabilization and H-RASv12 mutation) drives the formation of serially transplantable MLS. This is the first model of sarcoma based on the expression of a sarcoma-associated fusion protein in hMSC, and allowed us to unravel the differentiation processes and signaling pathways altered in the MLS-initiating cells. This study will contribute to test novel therapeutic approaches, and constitutes a proof-of-concept to employ hMSCs as target cell for modeling other fusion gene-associated human sarcomas. Wild type (MSC-0H) or transformed (MSC-5H) BM-hMSCs were transduced with concentrated viral particles expressing either pRRL-EF1?-PGK-GFP (empty vector; GFP) or pRRL-EF1?-FUS-CHOP-PGK-GFP (FUSCHOP expressing vector; FC) in order to generate MSC-0H-GFP, MSC-0H-FC, MSC-5H-GFP and MSC-5H-FC cell lines. MSC-0H-GFP and MSC-0H-FC cells did not develop tumors, meanwhile MSC-5H-GFP cells gave rise to undifferentiated sarcomas and MSC-5H-FC originated mixoid liposarcoma tumors when inoculated into immunedeficient mice. Several cell lines were derived from tumors developed from MSC-5H-GFP (T-5H-GFP-1 to -3 cell lines) and MSC-5H-FC (T-5H-FC-1 to -3 cell lines) cells. Gene expression analysis was performed using MSC-0H, MSC-5H and T-5H cell lines and lists of differentially expressed genes were created by comparing the gene expression profiles of MSC-0H-FC, MSC-5H-FC and T-5H-FC cell types to the control MSC-0H-GFP cells.

2013-06-18 | E-GEOD-48030 | biostudies-arrayexpress

Expression profiling of human umbilical cord mesenchymal stem cell line hMSCs, human esophageal carcinoma cell line EC9706 and their hybrids EMFs.

Project description:Our findings demonstrate that hMSCs can inhibit the malignant phenotypes of ECs through induced cell fusion without potentially cancerous reprogramming. To further understand the differences between before-after cell fusion and the mechanism of suppression, we used gene expression profiling technology from Capitalbio to find out the differences between EC cells, hMSCs and their derived heterokaryons. Six dual channel Capitalbio 22K Human oligo arrays was used to hybrid six paired samples (EC9706-cy3+EMF1-cy5, EC9706-cy3+EMF2-cy5, EC9706-cy3+EMF3-cy5, EMF1-cy3+hMSCs-cy5, EMF3-cy3+hMSC-cy5, hMSC-cy3+EMF2-cy5).One replicate per array.

2011-01-21 | E-GEOD-26765 | biostudies-arrayexpress

Modeling the initiation of Ewing sarcoma tumorigenesis in human Embryonic Stem Cells [expression array]

Project description:Ewing sarcoma family of tumors (ESFT) is a uniquely human, highly aggressive bone and soft tissue malignancy peaking during adolescence characterized by EWSR1/ETS rearrangements. EWSR1/FLI1 expression is only tolerated in embryonic and mesenchymal stem cells (hESC and hMSC, respectively) that, although acquire ESFT transcriptional signatures, are devoid of tumorigenic potential. Here we report that ectopic EWSR1/FLI1 expression in hESC allows in vivo differentiation towards the three germ layers. In vitro, teratoma-derived hMSCs are devoid of transformation abilities. In vivo, these hMSCs led to the generation of T-cell lymphomas and ESFT-like tumors, composed of small-round blue cells. This new experimental approach constitutes a testing bench for the biology of translocation-dependent developmental tumors, from acute lymphoblastic leukemia to a variety of sarcomas.

2022-12-31 | GSE140328 | GEO

Modeling the initiation of Ewing sarcoma tumorigenesis in human Embryonic Stem Cells [RNA-seq]

2022-12-31 | GSE141888 | GEO

Genome-wide pairwise analysis of normal and spontaneously transformed adipose tissue derived hMSCs

Project description:hMSCs are perspective source for applications in the field of regeneraitve medicine. Biosafety of cultivated in vitro multipotent cells prior transplantation is one of the important issues. Genome-wide pairwise expression analysis of normal and immortalized hMSCs was performed to determine aspects of spontaneous transformation and immortalization mechanisms during cultivation of hMSCs. Data has provided insight into functionally connected genes involved in spontaneous transformation of hMSCs in vitro. Multipotent stromal cells (MSCs) were isolated from adipose tissue samples obtained from 6 healthy donors. Total RNA was isolated from 6 normal and 6 donor-matched spontaneously transformed hMSC cultures in vitro for pair-wise global comparison.

2012-12-09 | E-GEOD-42809 | biostudies-arrayexpress

Effect of depletion of CTR9 on gene expression during early osteogenic differentiation of human primary mesenchymal stem cells

Project description:Cell-fate determination of human mesenchymal stem/stromal cells (hMSCs) is precisely regulated by lineage-specific transcription factors and epigenetic enzymes. We found that CTR9, a key scaffold subunit of Polymerase Associated Factor Complex (PAFc), selectively regulates hMSC differentiation to osteoblasts and chondrocytes, but not to adipocytes. An in vivo ectopic osteogenesis assay confirmed the essentiality of CTR9 in hMSC-derived bone formation. CTR9 counteracts the activity of EZH2, the epigenetic enzyme that deposits H3K27me3, in hMSCs. Accordingly, CTR9 knockdown (1) hMSCs gain H3K27me3 mark, and the osteogenic differentiation defects of CTR9 KD hMSCs can be partially rescued by treatment with EZH2 inhibitors. Transcriptome analyses identified Bone Morphology Protein-2 (BMP-2) as a downstream effector of CTR9. BMP-2 secretion, membrane anchorage, as well as the BMP-SMAD pathway were impaired in CTR9 KD MSCs, and the effects were rescued by BMP-2 supplementation. This study uncovers an epigenetic mechanism engaging CTR9-H3K27me3-BMP-2 axis to regulate osteochondral lineage differentiation of hMSCs. To investigate the function of CTR9 in the gene regulation of early osteogenic committment , we established human MSCs in which CTR9 gene has been knocked down by two individual shRNAs (shControl vs shCTR9#3/#5）.

2022-11-23 | GSE213277 | GEO

The Chimeric Oncoprotein TLS-CHOP Represses Expression of the Anticancer Cytokine MDA-7/IL-24 in Myxoid Liposarcoma Cells

Project description:The TLS-CHOP fusion protein is found in the majority of human myxoid liposarcomas (MLS), and is thought to have oncogenic functions. Until now, however, the molecular function of TLS-CHOP for oncogenesis is still elusive. In this report, we have revealed that knockdown of TLS-CHOP by specific siRNA in MLS-derived cell lines inhibits cell growth and leads to cell death. Thus, TLS-CHOP may be a promising therapeutic target for MLS treatment. Thus we explored the target genes of TLS-CHOP influence cell-proliferation or cell death with microarray.

2013-12-27 | GSE33616 | GEO

Stem Cell-Derived Matrices Provide Improved Isolation and Maintenance of hMSC Characteristics

Project description:Adult human mesenchymal stem cells (hMSCs) have shown promise as a valuable new therapeutic tool in a wide range of diseases. hMSCs from bone marrow stroma are currently isolated by their adherence to tissue culture treated polystyrene (TCP) and passaged multiple times on the same plastics until they are able to produce enough cells to be useful for research or clinical therapeutic trials. However, evidence in the literature has shown that culture on TCP can negatively alter hMSC function. Our aim was to expand hMSCs in an in vitro environment more closely resembling that of the hMSCs' native microenvironment to maximize proliferation while retaining therapeutic potential. We used decellularized hMSC-derived extracellular matrix (hMSC-ECM) to test hMSCs' maintenance of stem cell properties during in vitro expansion. We found that hMSC-ECM was able to increase hMSC proliferation while retaining the stem cells‘ immature state and increasing differentiation potential. In addition, the hMSC-ECM could be covalently cross-linked to polymer substrates and was effective in the isolation and expansion of hMSCs in the presence of fetal bovine serum and human serum. Using proteomics and transcriptomics, we were able to determine the mechanism behind the hMSCs’ increased proliferation was due to their ability to downregulate their otherwise required gene expression for ECM proteins by on hMSC-ECM. The effects of hMSC-ECM were largely hMSC specific and were not found with several other types of human cells. Providing a pre-formed in vitro niche for hMSCs can provide the cells with the critical components required for hMSC function during in vitro expansion.

2020-09-01 | GSE119096 | GEO

TLS-CHOP Fusion Oncoprotein Regulates MicroRNA-486 in Human Myxoid Liposarcoma

Project description:MicroRNAs (miRNAs, miRs) are small noncoding RNAs, which control or are controlled by the dysregulation of multiple protein-coding oncogenes or tumor suppressor genes, play important roles in carcinogenesis. Myxoid liposarcomas (MLS) are characterized by t(12;16)(q13;p11) translocation and expression of TLS/CHOP chimeric transcripts (various types) which encode different oncogenic proteins. TLS-CHOP is important for the molecular mechanisms in the development of MLS, but the involvement in microRNA expression still remain poorly understood. Thus we explored the target microRNA of TLS-CHOP influence cell-proliferation or cell death with microarray. MicroRNAs (miRNAs, miRs) are small noncoding RNAs, which control or are controlled by the dysregulation of multiple protein-coding oncogenes or tumor suppressor genes, play important roles in carcinogenesis. Myxoid liposarcomas (MLS) are characterized by t(12;16)(q13;p11) translocation and expression of TLS/CHOP chimeric transcripts (various types) which encode different oncogenic proteins. TLS-CHOP is important for the molecular mechanisms in the development of MLS, but the involvement in microRNA expression still remain poorly understood. In this study, we have found that miR-486-5p (miR-486) expression level was downregulated by ectopic expression of TLS-CHOP fusion gene in mouse fibroblast cells (NIH3T3). In addition, we found overexpression of miR-486 inhibited the cell growth in the 2645/94 cells and in situ hybridization of miR-486 showed MLS tissues had lower signal intensity compared with non-tumor tissues. Thus we explored the target genes of miR-486 influence cell-proliferation or cell death with microarray.

2013-03-23 | GSE36966 | GEO

A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion

Project description:The identification of subtype-specific translocations has revolutionized diagnostics of sarcoma and provided new insight into oncogenesis. We used RNA-Seq to investigate samples diagnosed as small round cell tumors of bone, possibly Ewing sarcoma, but lacking the canonical EWSR1-ETS translocation. A new fusion was observed between the BCL6 co-repressor (BCOR) and the testis specific cyclin B3 (CCNB3) genes on chromosome X. RNA-Seq results were confirmed by RT-PCR and cloning the tumor-specific genomic translocation breakpoints. 24 BCOR-CCNB3-positive tumors were identified among a series of 594 sarcomas. Gene profiling experiments indicate that BCOR-CCNB3-positive cases are biologically distinct from other sarcomas, particularly EwingM-bM-^@M-^Ys sarcoma. Finally, we show that CCNB3 immunohistochemistry is a powerful diagnostic marker for this group of sarcoma and that over-expression of BCOR-CCNB3 or of a truncated CCNB3 activates S-phase in NIH3T3 cells. Thus the intrachromosomal X fusion described here represents a new subtype of bone sarcoma caused by a novel gene fusion mechanism. Comparison of expression profiles of 10 BCOR-CCNB3 samples (plus 4 EWS-FLI1 Ewing sarcomas samples as control) with publicly available profiles of other tumor types.

2012-03-03 | E-GEOD-34800 | biostudies-arrayexpress

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