The Fusion Oncogene FUS-CHOP Drives Sarcomagenesis of High-Grade Spindle Cell Sarcomas in Mice

Chen, Mark; Xu, Eric S.; Leisenring, Nathan H.; Cardona, Diana M.; Luo, Lixia; Ma, Yan; Ventura, Andrea; Kirsch, David G.

doi:10.1155/2019/1340261

Cited by 11 publications

(9 citation statements)

References 44 publications

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“…This general mechanism of FET fusion-mediated chromatin remodeling may be a model for sarcomagenesis of an entire class of translocation-positive sarcomas that contain FET protein translocation partners. Additionally, to address lessons from modeling sarcomas in other organisms, this mechanism may explain why fusion-positive sarcomas are difficult to model in mice where the specific DNA-binding motifs and enhancers required for sarcomagenesis in humans differ from those required for these processes in mice (Chen et al, 2019;Minas et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…To further validate these interactions in a different organism, we performed co-IPs in mouse cell lines and mouse tumor cell lines with and without FUS-CHOP (fig. S1) (Chen et al, 2019;Kirsch et al, 2007). The FUS-CHOP-expressing tumor cell lines used for these experiments were derived from the conditional mouse model of FUS-CHOP-driven sarcoma that we generated using Cre and CRISPR/Cas9 technology (Chen et al, 2019).…”

Section: Fus-chop Interacts With the Baf And Iswi Chromatin Remodelinmentioning

confidence: 99%

“…S1) (Chen et al, 2019;Kirsch et al, 2007). The FUS-CHOP-expressing tumor cell lines used for these experiments were derived from the conditional mouse model of FUS-CHOP-driven sarcoma that we generated using Cre and CRISPR/Cas9 technology (Chen et al, 2019). FUS-CHOP coimmunoprecipitated with Snf2h and Brg1 in these mouse cell lines (fig.…”

Section: Fus-chop Interacts With the Baf And Iswi Chromatin Remodelinmentioning

confidence: 99%

“…To determine if SNF2H and BRG1 impact the proliferation of FUS-CHOP-expressing cells, we stably knocked down Snf2h and Brg1 in KP (KrasG12D; p53-/-) (Kirsch et al, 2007) and 1650 (FUS-CHOP positive) (Chen et al, 2019) mouse sarcoma cells ( Fig. 2A).…”

Section: Fus-chop-driven Sarcoma Cells Are Dependent On Snf2h and Brgmentioning

confidence: 99%

“…NIH-3T3 cell lines were purchased from ATCC (CRL-1658) and cultured in DMEM media (ThermoFisher Scientific, 11965092) supplemented with 10% fetal bovine serum (ThermoFisher Scientific, 16000044) and 1% antibiotic-antimycotic (ThermoFisher Scientific, 10091148), and incubated at 37°C with 5% CO2 in a humidified cell-culture incubator. Tumor cells were isolated from primary mouse sarcomas as previously described (Chen et al, 2019). Briefly, tumor tissue was minced in the cell-culture hood and digested by dissociation buffer in PBS (ThermoFisher Scientific, 14040133) containing collagenase type IV (5 mg/ml, ThermoFisher Scientific, 17104-019), dispase (1.3 mg/ml, ThermoFisher Scientific, 17105-041) as well as trypsin (0.05%, ThermoFisher Scientific, 25200056) for about 1 h at 37°C.…”

Section: Tissue Culture and Cell Line Generationmentioning

confidence: 99%

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Disruption of oncogenic targeting by ISWI via phosphorylation of a prion-like domain

Chen

Foster

Lock

et al. 2020

Preprint

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Chromosomal translocations generate oncogenic fusion proteins in approximately one-third of sarcomas, but how these proteins promote tumorigenesis and the effect of cancer therapies on their function are not well understood. Here, we reveal a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance that also explains the remarkable radiation sensitivity of myxoid liposarcomas. We identified novel interactions between FUS-CHOP and chromatin remodeling complexes that regulate sarcoma cell proliferation. One of these chromatin remodelers, SNF2H, co-localizes with FUS-CHOP genome-wide at active enhancers. Following ionizing radiation, DNA damage response kinases phosphorylate the prionlike domain of FUS-CHOP to impede these protein-protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupts oncogenic targeting of chromatin remodelers required for FUS-CHOP-driven sarcomagenesis. Significance:Prion-like domains translocated in cancer have been shown to drive global epigenetic changes that are oncogenic. However, some translocation-driven cancers exhibit dramatic clinical responses to therapy, though the mechanism for these responses are not well-understood. Here we show that ionizing radiation can disrupt oncogenic interactions between a fusion oncoprotein and a chromatin remodeling complex, ISWI. This mechanism of disruption links phosphorylation of the prion-like domain in an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma.(awards R35 CA197616 to DGK, F30 CA206424 to MC) and the T32 GM007171 MSTP training grant (Duke University).

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Section: Discussionmentioning

confidence: 99%

Section: Fus-chop Interacts With the Baf And Iswi Chromatin Remodelinmentioning

confidence: 99%

Section: Fus-chop Interacts With the Baf And Iswi Chromatin Remodelinmentioning

confidence: 99%

Section: Fus-chop-driven Sarcoma Cells Are Dependent On Snf2h and Brgmentioning

confidence: 99%

Section: Tissue Culture and Cell Line Generationmentioning

confidence: 99%

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Disruption of oncogenic targeting by ISWI via phosphorylation of a prion-like domain

Chen

Foster

Lock

et al. 2020

Preprint

Self Cite

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Liquid–liquid phase separation in diseases

Zhang,

Yuan,

Zhang

et al. 2024

MedComm

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Liquid–liquid phase separation (LLPS), an emerging biophysical phenomenon, can sequester molecules to implement physiological and pathological functions. LLPS implements the assembly of numerous membraneless chambers, including stress granules and P‐bodies, containing RNA and protein. RNA–RNA and RNA–protein interactions play a critical role in LLPS. Scaffolding proteins, through multivalent interactions and external factors, support protein–RNA interaction networks to form condensates involved in a variety of diseases, particularly neurodegenerative diseases and cancer. Modulating LLPS phenomenon in multiple pathogenic proteins for the treatment of neurodegenerative diseases and cancer could present a promising direction, though recent advances in this area are limited. Here, we summarize in detail the complexity of LLPS in constructing signaling pathways and highlight the role of LLPS in neurodegenerative diseases and cancers. We also explore RNA modifications on LLPS to alter diseases progression because these modifications can influence LLPS of certain proteins or the formation of stress granules, and discuss the possibility of proper manipulation of LLPS process to restore cellular homeostasis or develop therapeutic drugs for the eradication of diseases. This review attempts to discuss potential therapeutic opportunities by elaborating on the connection between LLPS, RNA modification, and their roles in diseases.

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Genetic drivers and cells of origin in sarcomagenesis

Kannan

Lock

Ozenberger

et al. 2021

The Journal of Pathology

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Sarcoma comprises a group of malignancies that includes over 100 individual disease entities. Type‐specific genetic events initiate each tumor, occurring within a specific cellular context or circumstance. All sarcomas share a relationship with mesenchymal tissues of origin. Conceptual models for each specific route towards sarcomagenesis have developed over the years as clinical, cellular, and increasingly molecular observations have advanced hypotheses to be tested in the forward or reverse direction in experimental systems, often genetically engineered model organisms. This review considers the history of these discoveries in the context of technologies available at the time each was made and provides a comprehensive summary of the current knowledge of sarcoma genetics, including characteristic translocations, oncogene activation and loss of tumor suppressor gene events, and their putative cells of origin. Also considered are the interrelatedness of molecular clinical observations and genetic experiments in model systems to move this field of knowledge forward, as well as their implications for diagnostic and therapeutic paradigms for sarcoma. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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The Fusion Oncogene FUS-CHOP Drives Sarcomagenesis of High-Grade Spindle Cell Sarcomas in Mice

Cited by 11 publications

References 44 publications

Disruption of oncogenic targeting by ISWI via phosphorylation of a prion-like domain

Disruption of oncogenic targeting by ISWI via phosphorylation of a prion-like domain

Liquid–liquid phase separation in diseases

Genetic drivers and cells of origin in sarcomagenesis

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