Mesenchymal gene program–expressing ovarian cancer spheroids exhibit enhanced mesothelial clearance

• DOI: 10.1172/jci69815
• Publication Date: 2014-04-28T18:04:27Z
• Authors: Rachel A. Davidowitz; Laura M. Selfors; Marcin P. Iwanicki; Kevin M. Elias; Alison Karst; Huiying Piao; Tan A. Ince; Michael G. Drage; Judy Dering; Gottfried E. Konecny; Ursula Matulonis; Gordon B. Mills; Dennis J. Slamon; Ronny Drapkin; Joan S. Brugge
• Keywords: Epithelial-Mesenchymal Transition; Immunology; Protein Array Analysis; Medical and Health Sciences; Epithelium; Mesoderm; 03 medical and health sciences; Rare Diseases; Spheroids, Cellular; Genetics; Tumor Cells, Cultured; 2.1 Biological and endogenous factors; Humans; Neoplasm Invasiveness; Aetiology; Peritoneal Neoplasms; Cancer; Homeodomain Proteins; Ovarian Neoplasms; 0303 health sciences; Cultured; Twist-Related Protein 1; Nuclear Proteins; Zinc Finger E-box-Binding Homeobox 1; Ovarian Cancer; Tumor Cells; 3. Good health; Gene Knockdown Techniques; Female; Cellular; Snail Family Transcription Factors; Spheroids; Transcriptome; Biotechnology; Transcription Factors

Metastatic dissemination of ovarian tumors involves the invasion of tumor cell clusters into the mesothelial cell lining of peritoneal cavity organs; however, the tumor-specific factors that allow ovarian cancer cells to spread are unclear. We used an in vitro assay that models the initial step of ovarian cancer metastasis, clearance of the mesothelial cell layer, to examine the clearance ability of a large panel of both established and primary ovarian tumor cells. Comparison of the gene and protein expression profiles of clearance-competent and clearance-incompetent cells revealed that mesenchymal genes are enriched in tumor populations that display strong clearance activity, while epithelial genes are enriched in those with weak or undetectable activity. Overexpression of transcription factors SNAI1, TWIST1, and ZEB1, which regulate the epithelial-to-mesenchymal transition (EMT), promoted mesothelial clearance in cell lines with weak activity, while knockdown of the EMT-regulatory transcription factors TWIST1 and ZEB1 attenuated mesothelial clearance in ovarian cancer cell lines with strong activity. These findings provide important insights into the mechanisms associated with metastatic progression of ovarian cancer and suggest that inhibiting pathways that drive mesenchymal programs may suppress tumor cell invasion of peritoneal tissues.