Speakers at ICG-13

Speakers at ICG-13

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Biography

A/Prof Oliver Sieber is Acting Joint Head of the Systems Biology and Personalised Medicine Division at the Walter and Eliza Hall Institute of Medical Research (WEHI). He has been Executive Editor of Genomics (Elsevier) since 2015. He completed his PhD in 2004 at the Imperial Cancer Research Fund Laboratories and Cancer Research UK. Prior to taking up his position at WEHI, he undertook 6 years postdoctoral training at Cancer Research UK, the University of Oxford and the Ludwig Institute for Cancer Research (LICR). He was Joint Laboratory Head and Assistant Member at the LICR, Parkville, from 2009-12. A/Prof Sieber's group aims to understand the molecular pathology of human colorectal cancer and to translate this knowledge into new diagnostic and therapeutic modalities.


Abstract

Colorectal Cancer Cell Lines as Tumour Models: A Proteogenomic Perspective

Jing Wang,1,2,* Dmitri Mouradov,3,4,* Xiaojing Wang,1,2,* Robert N. Jorissen,3,4 Matthew C. Chambers,5 Lisa J. Zimmerman,5 Suhas Vasaikar,1,2 Christopher G. Love,3,4 Shan Li,3 Kym Lowes,3 Karl-Johan Leuchowius,3 Helene Jousset,3 Janet Weinstock,6 Christopher Yau,7,8 John Mariadason,9,10 Zhiao Shi,1 Yuguang Ban,11 Xi Chen,11 Robert J. C. Coffey,12 Robbert J. C. Slebos,13 Antony W. Burgess,4,6 Daniel C. Liebler,5 Bing Zhang,1,2 and Oliver M. Sieber3,4

1Lester and Sue Smith Breast Center; 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; 3Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research; 4Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia; 5Department of Biochemistry, Vanderbilt University, Nashville, Tennessee; 6Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; 7Wellcome Trust Centre for Human Genetics; 8Department of Statistics, University of Oxford, Oxford, United Kingdom; 9Olivia Newton-John Cancer Research Institute, Heidelberg; 10La Trobe University School of Cancer Medicine, Melbourne, VIC, Australia; 11Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida; 12Department of Medicine, Vanderbilt University School of Medicine, Nashville; 13Clinical Science Lab, Moffitt Cancer Center, Tampa, Florida

Human tumour-derived cell lines are widely used to study cancer biology and therapy, but controversy remains whether cell lines provide appropriate representation of primary tumours. Here, we report an integrative proteogenomic analysis of human colorectal cancer (CRC) cell lines, primary tumours and corresponding normal tissues. We found that cell lines reflected the proteomic alterations of primary tumours, in particular when considering intrinsic cellular programs. Associations between protein expression and DNA copy number aberrations or signatures of post-transcriptional regulation were similar in cell lines and tumours. The five major proteomic subtypes previously detected in primary tumours were observed among cell lines. However, there were also differences between cell line and tumour proteomes which appeared largely attributable to stroma, extrinsic signalling, and growth conditions. The presence of stroma obscured signatures of DNA mismatch repair in tumours that were detectable in cell lines with a hypermutation phenotype. Integration of cell line proteogenomic data with drug sensitivity measurements demonstrated improved prediction of both known drug-target relationships and overall drug sensitivity as compared with genomic or transcriptomic modalities. In addition, there was evidence for differential drug responses depending on CRC proteomic subtype. Therapeutic targeting of proteins associated with drug responses identified respective synergistic or antagonistic drug combinations. Our findings highlight the potential of proteome profiling to inform both basic cancer research and drug development.

Wang J, Mouradov D, Wang X, Jorissen RN, Chambers MC, Zimmerman LJ, Vasaikar S, Love CG, Li S, Lowes K, Leuchowius KJ, Jousset H, Weinstock J, Yau C, Mariadason J, Shi Z, Ban Y, Chen X, Coffey RJC, Slebos RJC, Burgess AW, Liebler DC, Zhang B, Sieber OM. Colorectal cancer cell line proteomes are representative of primary tumors and predict drug sensitivity. Gastroenterology. 2017;153(4):1082-1095.

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