CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs
Ross A. Okimoto, Wei Wu, Shigeki Nanjo, Victor Olivas, Yone K. Lin, Rovingaile Kriska Ponce, Rieko Oyama, Tadashi Kondo, Trever G. Bivona
Ross A. Okimoto, Wei Wu, Shigeki Nanjo, Victor Olivas, Yone K. Lin, Rovingaile Kriska Ponce, Rieko Oyama, Tadashi Kondo, Trever G. Bivona
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Concise Communication Oncology

CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs

Abstract

Transcription factor fusion genes create oncoproteins that drive oncogenesis and represent challenging therapeutic targets. Understanding the molecular targets by which such fusion oncoproteins promote malignancy offers an approach to develop rational treatment strategies to improve clinical outcomes. Capicua–double homeobox 4 (CIC-DUX4) is a transcription factor fusion oncoprotein that defines certain undifferentiated round cell sarcomas with high metastatic propensity and poor clinical outcomes. The molecular targets regulated by the CIC-DUX4 oncoprotein that promote this aggressive malignancy remain largely unknown. We demonstrated that increased expression of ETS variant 4 (ETV4) and cyclin E1 (CCNE1) occurs via neomorphic, direct effects of CIC-DUX4 and drives tumor metastasis and survival, respectively. We uncovered a molecular dependence on the CCNE-CDK2 cell cycle complex that renders CIC-DUX4–expressing tumors sensitive to inhibition of the CCNE-CDK2 complex, suggesting a therapeutic strategy for CIC-DUX4–expressing tumors. Our findings highlight a paradigm of functional diversification of transcriptional repertoires controlled by a genetically aberrant transcriptional regulator, with therapeutic implications.

Authors

Ross A. Okimoto, Wei Wu, Shigeki Nanjo, Victor Olivas, Yone K. Lin, Rovingaile Kriska Ponce, Rieko Oyama, Tadashi Kondo, Trever G. Bivona

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Figure 1

ETV4 promotes metastasis in CIC-DUX4–expressing sarcoma.

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ETV4 promotes metastasis in CIC-DUX4–expressing sarcoma. (A) Schematic o...
(A) Schematic of the orthotopic soft tissue metastasis model. (B) Representative bioluminescence (BLI) images from mice bearing CIC-DUX4–expressing NIH 3T3 cells with shCtrl (n = 9) or shETV4 (n = 7). (C) Immunoblot of ETV4 and MMP24 from NIH 3T3 cells expressing empty vector (EV), shCtrl, shETV4a, or shETV4b. (D) Number of lung metastases in mice bearing CIC-DUX4–expressing NIH 3T3 cells with shCtrl (n = 9) or shETV4 (n = 7). P value, Student’s t test. (E) Transwell invasion assay comparing CIC-DUX4–expressing NIH 3T3 cells with EV, shCtrl, shETV4a, or shETV4b. P value, 1-way ANOVA. Error bars represent SEM. (F) Relative photon flux from mice orthotopically implanted with CIC-DUX4–expressing NIH 3T3 cells expressing either shCtrl or shETV4. Error bars reflect SEM. (G) Subcutaneously implanted NIH 3T3 cells with EV, CIC-DUX4, or CIC-DUX4 plus shETV4a or shETVb. P value, 1-way ANOVA. Error bars represent SEM.