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Assessment of Ovarian Cancer Spheroid Attachment and Invasion of Mesothelial Cells in Real Time
Published on: May 20, 2014
The STAT3-miRNA-92-Wnt Signaling Pathway Regulates Spheroid Formation and Malignant Progression in Ovarian Cancer
Min-Wei Chen1, Shu-Ting Yang2, Ming-Hsien Chien3,4
1Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
Abstract:
Ovarian cancer spheroids constitute a metastatic niche for transcoelomic spread that also engenders drug resistance. Spheroid-forming cells express active STAT3 signaling and display stem cell-like properties that may contribute to ovarian tumor progression. In this study, we show that STAT3 is hyperactivated in ovarian cancer spheroids and that STAT3 disruption in this setting is sufficient to relieve chemoresistance. In an NSG murine model of human ovarian cancer, STAT3 signaling regulated spheroid formation and self-renewal properties, whereas STAT3 attenuation reduced tumorigenicity. Mechanistic investigations revealed that Wnt signaling was required for STAT3-mediated spheroid formation. Notably, the Wnt antagonist DKK1 was the most strikingly upregulated gene in response to STAT3 attenuation in ovarian cancer cells. STAT3 signaling maintained stemness and interconnected Wnt/β-catenin signaling via the miR-92a/DKK1-regulatory pathways. Targeting STAT3 in combination with paclitaxel synergistically reduced peritoneal seeding and prolonged survival in a murine model of intraperitoneal ovarian cancer. Overall, our findings define a STAT3-miR-92a-DKK1 pathway in the generation of cancer stem-like cells in ovarian tumors, with potential therapeutic applications in blocking their progression. Cancer Res; 77(8); 1955-67. ©2017 AACR.
Insights
Targeting STAT3 signaling in ovarian cancer spheroids overcomes drug resistance and reduces tumor spread. This pathway involves Wnt/β-catenin signaling and stemness, offering new therapeutic strategies for ovarian cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Stem Cell Research
Background:
- Ovarian cancer spheroids promote metastasis and drug resistance.
- Spheroid-forming cells exhibit STAT3 signaling and stem cell-like properties, contributing to tumor progression.
Purpose of the Study:
- Investigate the role of STAT3 signaling in ovarian cancer spheroids.
- Determine the mechanisms by which STAT3 influences spheroid formation, stemness, and chemoresistance.
- Evaluate therapeutic strategies targeting STAT3 in ovarian cancer models.
Main Methods:
- Analysis of STAT3 activation in ovarian cancer spheroids.
- Utilizing an NSG murine model of human ovarian cancer to study STAT3's role in spheroid formation, self-renewal, and tumorigenicity.
- Investigating the interplay between STAT3, Wnt signaling, and miR-92a/DKK1 pathways.
- Assessing the synergistic effect of targeting STAT3 with paclitaxel in vivo.
Main Results:
- STAT3 is hyperactivated in ovarian cancer spheroids, and its disruption alleviates chemoresistance.
- STAT3 signaling regulates spheroid formation and self-renewal in a murine model, with STAT3 attenuation reducing tumorigenicity.
- Wnt signaling is essential for STAT3-mediated spheroid formation, and DKK1 is upregulated upon STAT3 attenuation.
- STAT3 maintains stemness by interconnecting Wnt/β-catenin signaling through miR-92a/DKK1 pathways.
Conclusions:
- A STAT3-miR-92a-DKK1 pathway is identified in generating cancer stem-like cells in ovarian tumors.
- Targeting STAT3, particularly in combination with chemotherapy, shows promise for blocking ovarian cancer progression and improving survival.
- These findings offer potential therapeutic applications for overcoming drug resistance and metastasis in ovarian cancer.
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