Dynamic differences between DNA damage repair responses in primary tumors and cell lines
| Autor: | Rajni Sonavane, Ganesh V. Raj, Aditya Bagrodia, Anvita Devineni, Ralf Kittler, Yi Yin, Lan Yu, Collin Gilbreath, Carlos M. Roggero, Shihong Ma, Neil Desai, Ryan Mauck |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research patient-derived explant Biology DNA damage response DNA repair lcsh:RC254-282 03 medical and health sciences Prostate cancer 0302 clinical medicine Prostate medicine Gene Original Research Ex vivo culture Kidney Tumor microenvironment radiation resistance medicine.disease DNA Damage Repair lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens body regions 030104 developmental biology medicine.anatomical_structure Oncology Cell culture 030220 oncology & carcinogenesis Cancer research Ex vivo |
| Zdroj: | Translational Oncology, Vol 14, Iss 1, Pp 100898-(2021) Translational Oncology |
| ISSN: | 1936-5233 |
| Popis: | The study of DNA damage repair response (DDR) in prostate cancer is restricted by the limited number of prostate cancer cell lines and lack of surrogates for heterogeneity in clinical samples. Here, we sought to leverage our experience with patient derived explants (PDEs) cultured ex vivo to study dynamics of DDR in primary tumors following application of clinically relevant doses of ionizing radiation (IR) to tumor cells in their native 3-dimensional microenvironment. We compared DDR dynamics between prostate cancer cell lines, PDEs and xenograft derived explants (XDEs) following treatment with IR (2Gy) either alone or in combination with pharmacological modulators of DDR. We have shown that following treatment with 2Gy, DDR can be consistently detected in PDEs from multiple solid tumors, including prostate, kidney, testes, lung and breast, as evidenced by γ-H2AX, 53BP1, phospho-ATM and phospho-DNA-PKcs foci. By examining kinetics of resolution of IR-induced foci, we have shown that DDR in prostate PDEs (complete resolution in 8 h) is much faster than in prostate cancer cell lines ( Highlights • IR induces distinct DNA damage repair kinetics in prostate cancer PDEs and cell lines. • IR induces a distinct transcriptional program in prostate cancer PDE and cell lines. • DNA-PKcs inhibition blocks IR-induced DDR in prostate cancer PDE. • Inhibition of AR impairs NHEJ in prostate cancer PDEs. |
| Databáze: | OpenAIRE |
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