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Proteomic analysis reveals a role for PAX8 in peritoneal colonization of high grade serous ovarian cancer that can be targeted with micelle encapsulated thiostrepton

Oncogene volume 38, pages 6003–6016 (2019)Cite this article

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Abstract

High grade serous ovarian cancer (HGSOC) is the fifth leading cause of cancer deaths among women yet effective targeted therapies against this disease are limited. The heterogeneity of HGSOC, including few shared oncogenic drivers and origination from both the fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE), has hampered development of targeted drug therapies. PAX8 is a lineage-specific transcription factor expressed in the FTE that is also ubiquitously expressed in HGSOC where it is an important driver of proliferation, migration, and cell survival. PAX8 is not normally expressed in the OSE, but it is turned on after malignant transformation. In this study, we use proteomic and transcriptomic analysis to examine the role of PAX8 leading to increased migratory capabilities in a human ovarian cancer model, as well as in tumor models derived from the OSE and FTE. We find that PAX8 is a master regulator of migration with unique downstream transcriptional targets that are dependent on the cell’s site of origin. Importantly, we show that targeting PAX8, either through CRISPR genomic alteration or through drug treatment with micelle encapsulated thiostrepton, leads to a reduction in tumor burden. These findings suggest PAX8 is a unifying protein driving metastasis in ovarian tumors that could be developed as an effective drug target to treat HGSOC derived from both the OSE and FTE.

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Acknowledgements

This work was supported by the Department of Defense Ovarian Cancer Fund 160076, the National Cancer Institute F30CA224986, the National Cancer Center for Research Resources Facilities Improvement Program C06RR15482, the University of Illinois-Chicago Department of Chemistry, the Ara Parsegian Medical Research Foundation, and the Abraham Lincoln Fellowship.

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Author notes

  1. These authors contributed equally: Melissa R. Pergande, Karina Esparaza

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA

    Laura R. Hardy, Kimberly N. Heath & Joanna E. Burdette

  2. Department of Chemistry, University of Illinois at Chicago, Chicago, IL, USA

    Melissa R. Pergande & Stephanie M. Cologna

  3. Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA

    Karina Esparza & Hayat Önyüksel

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  1. Laura R. Hardy
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Correspondence to Joanna E. Burdette.

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Supplementary information

Supplemental figure legends

Supplemental Figure 1. Verification of modified cell lines generated in this study by immunoblot

Supplemental Figure 2. Heterozygous deletion of PAX8 in OVCAR8 reduces epithelial markers

Supplemental Figure 3. PAX8 deletion does not affect proliferation in OVCAR8<sup>RFP</sup> cells

Supplemental Figure 4. PAX8 does not affect adherens junctions in OVCAR8<sup>RFP</sup> cel

Supplemental Figure 5. PAX8 does not regulate PKCα in MOSE cells

Supplemental Table 1. Antibodies used in this study

Supplemental Table 2. OVCAR8 proteome with PAX8 alteration

Supplemental Table 3. MOSE proteome with PAX8 alteration

Supplemental Table 4. List of proteins differentially regulated by PAX8 in MOSE and OVCAR8 cell lines

Supplemental Table 5. Transcriptome of MOSE cells with PAX8 overexpressed

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Hardy, L.R., Pergande, M.R., Esparza, K. et al. Proteomic analysis reveals a role for PAX8 in peritoneal colonization of high grade serous ovarian cancer that can be targeted with micelle encapsulated thiostrepton. Oncogene 38, 6003–6016 (2019). https://doi.org/10.1038/s41388-019-0842-2

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