Dynamic differences between DNA damage repair responses in primary tumors and cell lines

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Studying DNA damage repair (DDR) in prostate cancer is challenging due to limited cell lines and lack of clinical sample surrogates.
• Existing models do not fully capture the complexity of tumor heterogeneity and the 3D microenvironment.

Purpose of the Study:

• To leverage patient-derived explants (PDEs) cultured ex vivo to study DDR dynamics in primary prostate tumors.
• To compare DDR dynamics in PDEs, cell lines, and xenograft-derived explants (XDEs) following ionizing radiation (IR) and drug modulation.

Main Methods:

• Cultured patient-derived explants (PDEs) and prostate cancer cell lines.
• Treated samples with 2Gy ionizing radiation (IR), alone and with DDR-targeting drugs.
• Assessed DDR by quantifying foci of DNA repair markers (γ-H2AX, 53BP1, phospho-ATM, phospho-DNA-PKcs) and analyzing transcriptional profiles.

Main Results:

• DDR was consistently detected in PDEs from various solid tumors (prostate, kidney, testes, lung, breast) post-IR.
• Prostate PDEs exhibited significantly faster DDR resolution (complete in 8h) compared to prostate cancer cell lines (<50% resolution in 8h).
• Transcriptional profiles of DDR genes and drug-modulated DDR kinetics differed between PDEs and cell lines.

Conclusions:

• Patient-derived explants (PDEs) provide a robust ex vivo model for studying DDR in primary solid tumors within their native microenvironment.
• PDEs offer a more accurate representation of in vivo DDR dynamics than traditional cell lines, aiding in the evaluation of therapeutic strategies.