NEDD9 promotes oncogenic signaling, a stem/mesenchymal gene signature, and aggressive ovarian cancer growth in mice

Abstract

Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) supports oncogenic signaling in a number of solid and hematologic tumors. Little is known about the role of NEDD9 in ovarian carcinoma (OC), but available data suggest elevated mRNA and protein expression in advanced stage high-grade cancers. We used a transgenic MISIIR-TAg mouse OC model combined with genetic ablation of Nedd9 to investigate its action in the development and progression of OC. A Nedd9−/− genotype delayed tumor growth rate, reduced incidence of ascites, and reduced expression and activation of signaling proteins including SRC, STAT3, E-cadherin, and AURKA. Cell lines established from MISIIR-TAg;Nedd9−/− and MISIIR-TAg;Nedd9+/+ mice exhibited altered migration and invasion. Growth of these cells in a syngeneic allograft model indicated that systemic Nedd9 loss in the microenvironment had little impact on tumor allograft growth, but in a Nedd9 wild-type background Nedd9−/− allografts exhibited significantly reduced growth, dissemination, and oncogenic signaling compared to Nedd9+/+ allografts. Gene expression analysis revealed that Nedd9+/+ tumors exhibited more mesenchymal “stem-like” transcriptional program, including increased expression of Aldh1a1 and Aldh1a2. Conversely, loss of Nedd9 resulted in increased expression of differentiation genes, including fallopian tube markers Foxj1, Ovgp1, and Pax8. Collectively, these data suggest that tumor cell-intrinsic Nedd9 expression promotes OC development and progression by broad induction of oncogenic protein signaling and stem/mesenchymal gene expression.

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Acknowledgements

The authors gratefully acknowledge Drs. Zeng-jie Yang and David Schlaepfer for helpful discussions; Dr. Eric Ross and Ms. Lyudmila DeMora of the FCCC Biostatistics and Bioinformatics Facility for helpful discussions and statistical analysis; Ms. Ellen Neulight for assistance with genotyping transgenic mice; Ms. Jane Miglo for technical assistance; and Mr. Xiang Hua in the Transgenic Mouse Facility for assistance with intrabursal injections. This work was supported by the FCCC Laboratory Animal, High Throughput Screening, Cell Culture, Biosample Repository, Biomedical Imaging, Flow Cytometry, Genomics, Histopathology, Transgenic Mouse and Biostatistics and Bioinformatics Facilities.

Funding

This work was supported by R01 CA136596 (to DCC); R01 CA63366 (to EAG); Ovarian SPORE P50 CA083638, the FCCC Core Grant NCI P30 CA006927, and charitable donations from the Roberta Dubrow Fund, the Teal Tea Foundation, and the Bucks County Board of Associates (to DCC).

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Correspondence to Denise C. Connolly.

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Gabbasov, R., Xiao, F., Howe, C.G. et al. NEDD9 promotes oncogenic signaling, a stem/mesenchymal gene signature, and aggressive ovarian cancer growth in mice. Oncogene 37, 4854–4870 (2018). https://doi.org/10.1038/s41388-018-0296-y

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