YAP1 and COX2 Coordinately Regulate Urothelial Cancer Stem-like Cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Stem Cell Research

Background:

• Acquired drug resistance is a major challenge in treating urothelial carcinoma of the bladder (UCB).
• Cancer stem-like cells (CSCs) are implicated in drug resistance, but the underlying mechanisms require further elucidation.
• Understanding CSC regulation is crucial for developing effective UCB therapies.

Purpose of the Study:

• To investigate the cooperative roles of COX2/PGE2 and YAP1 pathways in urothelial CSC expansion and drug resistance.
• To identify molecular mechanisms linking these pathways to CSC maintenance.
• To evaluate the therapeutic potential of dual COX2 and YAP1 inhibition in UCB.

Main Methods:

• Analysis of UCB clinical specimens for SOX2, COX2, and YAP1 expression.
• Investigating the effects of COX2/PGE2 and YAP1 on let-7 methylation and SOX2 expression.
• Utilizing a mouse xenograft model of UCB to assess therapeutic responses to dual inhibition.
• Evaluating CSC expansion after chemotherapy and EGFR inhibition.

Main Results:

• COX2/PGE2 and YAP1 pathways cooperate to expand urothelial CSCs by upregulating SOX2.
• COX2/PGE2 signaling downregulates let-7 via promoter methylation, leading to SOX2 upregulation.
• YAP1 directly enhances SOX2 expression.
• Coexpression of COX2, YAP1, and SOX2 correlates with UCB progression and EGFR inhibitor resistance.
• Dual inhibition of COX2 and YAP1 in a UCB xenograft model resulted in sustained therapeutic response by limiting CSCs.

Conclusions:

• The proinflammatory COX2/PGE2 pathway and YAP1 pathway synergistically promote urothelial CSC expansion and drug resistance.
• Targeting both COX2 and YAP1 concurrently with chemotherapy offers a promising strategy to overcome acquired resistance in UCB.
• These findings provide a preclinical rationale for combined therapeutic approaches in UCB management.