Three-dimensional CRISPR screening reveals epigenetic interaction with anti-angiogenic therapy.

Autor: He MY; Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Halford MM; Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Liu R; Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia., Roy JP; Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia., Grant ZL; Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.; Gladstone Institutes, San Francisco, CA, USA., Coultas L; Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia., Thio N; Bioinformatics Core, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Gilan O; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.; Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Chan YC; Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Dawson MA; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.; Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Centre for Cancer Research, The University of Melbourne, Parkville, VIC, Australia.; Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Achen MG; Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.; Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.; St Vincent's Institute of Medical Research, Melbourne, VIC, Australia., Stacker SA; Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Steven.Stacker@petermac.org.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. Steven.Stacker@petermac.org.; Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia. Steven.Stacker@petermac.org.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2021 Jul 15; Vol. 4 (1), pp. 878. Date of Electronic Publication: 2021 Jul 15.
DOI: 10.1038/s42003-021-02397-3
Abstrakt: Angiogenesis underlies development, physiology and pathogenesis of cancer, eye and cardiovascular diseases. Inhibiting aberrant angiogenesis using anti-angiogenic therapy (AAT) has been successful in the clinical treatment of cancer and eye diseases. However, resistance to AAT inevitably occurs and its molecular basis remains poorly understood. Here, we uncover molecular modifiers of the blood endothelial cell (EC) response to a widely used AAT bevacizumab by performing a pooled genetic screen using three-dimensional microcarrier-based cell culture and CRISPR-Cas9. Functional inhibition of the epigenetic reader BET family of proteins BRD2/3/4 shows unexpected mitigating effects on EC survival and/or proliferation upon VEGFA blockade. Moreover, transcriptomic and pathway analyses reveal an interaction between epigenetic regulation and anti-angiogenesis, which may affect chromosomal structure and activity in ECs via the cell cycle regulator CDC25B phosphatase. Collectively, our findings provide insight into epigenetic regulation of the EC response to VEGFA blockade and may facilitate development of quality biomarkers and strategies for overcoming resistance to AAT.
(© 2021. The Author(s).)
Databáze: MEDLINE
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