Abstract
Myxoid liposarcomas (MLS), malignant tumors of adipocyte origin, are driven by the FUS‐DDIT3 fusion gene encoding an aberrant transcription factor. The mechanisms whereby FUS‐DDIT3 mediates sarcomagenesis are incompletely understood, and strategies to selectively target MLS cells remain elusive. Here we show, using an unbiased functional genomic approach, that FUS‐DDIT3‐expressing mesenchymal stem cells and MLS cell lines are dependent on YAP1, a transcriptional co‐activator and central effector of the Hippo pathway involved in tissue growth and tumorigenesis, and that increased YAP1 activity is a hallmark of human MLS. Mechanistically, FUS‐DDIT3 promotes YAP1 expression, nuclear localization, and transcriptional activity and physically associates with YAP1 in the nucleus of MLS cells. Pharmacologic inhibition of YAP1 activity impairs the growth of MLS cells in vitro and in vivo. These findings identify overactive YAP1 signaling as unifying feature of MLS development that could represent a novel target for therapeutic intervention.
Highlights
Myxoid liposarcomas (MLS) account for 5–10% of soft-tissue sarcomas and approximately 20% of malignant adipocytic tumors (Fletcher et al, 2013)
We first integrated the data obtained in SCP-1 cells with the results of previous DECIPHER screens conducted in cell lines representing a range of hematopoietic
Fractionation experiments followed by immunoblotting as well as IF analysis demonstrated that YAP1 was primarily localized in the nucleus of MLS cells, indicating transcriptional activity, whereas in SW872 cells the majority of YAP1 protein was retained in the cytoplasm (Fig 2B, Appendix Fig S2B)
Summary
Myxoid liposarcomas (MLS) account for 5–10% of soft-tissue sarcomas and approximately 20% of malignant adipocytic tumors (Fletcher et al, 2013). In the majority of cases, MLS arises in younger adults, representing the most frequent liposarcoma subtype in patients below the age of 20 years. MLS are characterized by a high rate of local recurrence and development of distant metastases in approximately 40% of patients (Dei Tos, 2014). MLS comprise a broad spectrum of subtypes ranging from paucicellular myxoid tumors to hypercellular, round-cell high-grade sarcomas associated with a more aggressive clinical course (Antonescu et al, 2001). The vast majority of MLS are characterized by a t(12;16)(q13;p11) chromosomal translocation that juxtaposes parts of the FUS gene to the entire coding sequence of DDIT3. The resulting FUS-DDIT3 fusion protein, which acts as a transcriptional (dys-)regulator, has been shown to play an essential role in MLS pathogenesis
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