ETV4 and ETV5 drive synovial sarcoma through cell cycle and DUX4 embryonic pathway control
Joanna DeSalvo, … , Jonathan C. Trent, Josiane E. Eid
Joanna DeSalvo, … , Jonathan C. Trent, Josiane E. Eid
Published May 13, 2021
Citation Information: J Clin Invest. 2021;131(13):e141908. https://doi.org/10.1172/JCI141908.
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Research Article Oncology

ETV4 and ETV5 drive synovial sarcoma through cell cycle and DUX4 embryonic pathway control

Abstract

Synovial sarcoma is an aggressive malignancy with no effective treatments for patients with metastasis. The synovial sarcoma fusion SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGF receptor (FGFR) signaling. In genetic FGFR-knockout models, culture, and xenograft synovial sarcoma models treated with the FGFR inhibitor BGJ398, we show that FGFR1, FGFR2, and FGFR3 were crucial for tumor growth. Transcriptome analyses of BGJ398-treated cells and histological and expression analyses of mouse and human synovial sarcoma tumors revealed prevalent expression of two ETS factors and FGFR targets, ETV4 and ETV5. We further demonstrate that ETV4 and ETV5 acted as drivers of synovial sarcoma growth, most likely through control of the cell cycle. Upon ETV4 and ETV5 knockdown, we observed a striking upregulation of DUX4 and its transcriptional targets that activate the zygotic genome and drive the atrophy program in facioscapulohumeral dystrophy patients. In addition to demonstrating the importance of inhibiting all three FGFRs, the current findings reveal potential nodes of attack for the cancer with the discovery of ETV4 and ETV5 as appropriate biomarkers and molecular targets, and activation of the embryonic DUX4 pathway as a promising approach to block synovial sarcoma tumors.

Authors

Joanna DeSalvo, Yuguang Ban, Luyuan Li, Xiaodian Sun, Zhijie Jiang, Darcy A. Kerr, Mahsa Khanlari, Maria Boulina, Mario R. Capecchi, Juha M. Partanen, Lin Chen, Tadashi Kondo, David M. Ornitz, Jonathan C. Trent, Josiane E. Eid

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Figure 5

ETV4 and ETV5 expression in SS tumors.

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ETV4 and ETV5 expression in SS tumors. (A) Immunoblot shows ETV4 and ETV...
(A) Immunoblot shows ETV4 and ETV5 levels in SS18-SSX2–expressing C2C12 myoblasts. Vector is backbone control vector (POZ; see Supplemental Methods). SS18-SSX2 was visualized with anti-FLAG antibody. Actin served as loading control. (B–D) ETV4 and ETV5 IHC staining in tumors resected from two SS patients. Scale bars on the inset images: 50 μm; all other scale bars: 500 μm. (E–G) Representative images of ETV4 and ETV5 expression in tumors derived from SM2, SMF1.HO, SMF2.HO, and SMF3.HO mice. Scale bars: 20 μm. (H–J) Box plots show fold expression of ETV4 (H), ETV5 (I), and Tle1 (J) in the indicated tumor models over tissue derived from control mice. Two mice in each group were used for RNA isolation. The 12 overlaid dots in each box indicate individual values normalized against Gapdh and plotted as fold change over control. Data are derived from 2 RT-qPCR experiments performed in 6 replicates. Red crossbars indicate the mean. Error bars indicate SEM. P values compare average expression in each model against average expression in control tissues. *P < 0.00001; **P ≤ 0.00065; ***P ≤ 0.0019. ANOVA F ratios and corresponding P values shown on top demonstrate significant variation of means among the 4 groups in each plot.