Journal article

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

Michael Y He, Michael M Halford, Ruofei Liu, James P Roy, Zoe L Grant, Leigh Coultas, Niko Thio, Omer Gilan, Yih-Chih Chan, Mark A Dawson, Marc G Achen, Steven A Stacker



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 surviva..

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Funding Acknowledgements

We thank the following Peter MacCallum Cancer Centre core facilities: Ralph Rossi and staff at Flow Cytometry, Gisela Mir Arnau and staff at Molecular Genomics, and Jason Li and staff at Bioinformatics, for technical support and assistance on data analysis. This study was supported by Program Grants from the National Health and Medical Research Council of Australia (NHMRC) and by funds from the Operational Infrastructure Support Program provided by the Victorian Government, Australia. S.A.S. and M.G.A. are supported by a Senior Research Fellowship from the NHMRC. M.Y.H. was supported by a University of Melbourne Postgraduate Scholarship from the University of Melbourne, Australia; Z.L.G. by an Australian Government Research Training Program Scholarship and L.C. by the L.E.W. Carty Charitable Fund.