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

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.

• Authors: Laura R Hardy, Melissa R Pergande, Karina Esparza, Kimberly N Heath, Hayat Önyüksel, Stephanie M Cologna, Joanna E Burdette
• Journal: Oncogene (Oncogene) Vol. 38 Issue 32 Pg. 6003-6016 (08 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 31296958 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Micelles
• PAX8 Transcription Factor
• Pax8 protein, mouse
• Proteome
• Thiostrepton

Topics

• Animals
• Cell Adhesion (drug effects, genetics)
• Cell Movement (drug effects, genetics)
• Cells, Cultured
• Cystadenocarcinoma, Serous (drug therapy, genetics, pathology)
• Drug Compounding
• Drug Delivery Systems (methods)
• Fallopian Tubes (pathology)
• Female
• Gene Expression Profiling
• Mice
• Mice, Nude
• Micelles
• Neoplasm Grading
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• PAX8 Transcription Factor (genetics, physiology)
• Peritoneum (drug effects, metabolism, pathology)
• Proteome (analysis, metabolism)
• Proteomics
• Thiostrepton (administration & dosage, pharmacology)