LKB1 and STRADα Promote Epithelial Ovarian Cancer Spheroid Cell Invasion.

Area of Science:

• Oncology
• Cell Biology
• Molecular Biology

Background:

• Late-stage epithelial ovarian cancer (EOC) is characterized by widespread peritoneal dissemination, often involving ascites.
• EOC metastasis depends on the formation of multicellular aggregates known as spheroids.
• Liver Kinase B1 (LKB1) is essential for EOC spheroid viability, and its loss reduces tumor burden in preclinical models.

Purpose of the Study:

• To investigate the role of the LKB1 complex in controlling the invasive properties of human EOC spheroids.
• To determine how LKB1 and its activator STRAD influence EOC cell invasion and metastasis.

Main Methods:

• CRISPR/Cas9 knockout of LKB1 and RNAi targeting STRAD were used to antagonize LKB1 signaling.
• Real-time invasion monitoring using Matrigel, Transwell assays, spheroid reattachment, and mesothelial clearance assays were performed.
• Zymographic and 3D organoid models were employed to assess matrix metalloproteinase (MMP) activity and overall organoid growth.

Main Results:

• Loss of LKB1 and STRAD signaling significantly reduced EOC spheroid invasion through Matrigel and Transwell membranes.
• Mesothelial cell clearance was diminished in the absence of LKB1 and STRAD.
• LKB1 loss decreased MMP activity, while fibronectin restored spheroid invasiveness; 3D organoid area was also reduced.

Conclusions:

• LKB1 and STRAD signaling are critical for EOC metastasis, promoting invasion via MMP activity and fibronectin expression.
• Targeting the LKB1 pathway, including LKB1 and STRAD, presents a potential therapeutic strategy to inhibit EOC dissemination.