Modulating DNA damage response in uveal melanoma through embryonic stem cell microenvironment

Area of Science:

• Oncology
• Molecular Biology
• Stem Cell Research

Background:

• Uveal melanoma (UVM) is the most common adult intraocular tumor, with poor survival post-metastasis.
• UVM exhibits treatment resistance due to upregulated DNA damage response (DDR), often linked to PI3K/AKT pathway activation.
• Embryonic stem cell microenvironments (ESCMe) have shown potential in reverting cancer cells to less aggressive states by downregulating PI3K signaling, impacting UVM's DDR.

Purpose of the Study:

• Investigate the role of nonhomologous end joining (NHEJ)-related genes in UVM progression and prognosis.
• Evaluate the therapeutic potential of ESC transplantation and ESC-conditioned medium (ESC-CM) on DNA repair pathways in UVM.
• Assess the impact of ESC microenvironments on DDR and apoptosis in UVM models.

Main Methods:

• Gene expression and survival prognosis analysis using public UVM databases.
• Xenograft mouse models for assessing ESC-based therapies on DNA repair pathways.
• Quantitative PCR, immunohistochemistry, and TUNEL assays to analyze NHEJ gene expression and apoptosis.

Main Results:

• PRKDC, KU70, XRCC5, LIG4, and PARP1 expression correlated with UVM progression; specific genes predicted survival outcomes.
• ESCMe treatment significantly inhibited the NHEJ pathway and promoted apoptosis in UVM xenografts.
• ESC transplantation enhanced DDR in normal surrounding tissues, potentially reducing therapy side effects, with direct cell contact being more effective than secreted factors.

Conclusions:

• NHEJ-related genes are potential prognostic markers and therapeutic targets for UVM.
• ESC-based therapy shows promise in increasing UVM sensitivity to radiochemotherapy.
• ESC therapy could improve treatment outcomes while minimizing damage to healthy tissues.