The growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment. To date, molecular profiling has largely been restricted to the epithelial component of tumors; therefore, features underpinning the persistent protumorigenic phenotype of the tumor microenvironment are unknown. Using whole-genome bisulfite sequencing, we show for the first time that cancer-associated fibroblasts (CAFs) from localized prostate cancer display remarkably distinct and enduring genome-wide changes in DNA methylation, significantly at enhancers and promoters, compared to nonmalignant prostate fibroblasts (NPFs). Differentially methylated regions associated with changes in gene expression have cancer-related functions and accurately distinguish CAFs from NPFs. Remarkably, a subset of changes is shared with prostate cancer epithelial cells, revealing the new concept of tumor-specific epigenome modifications in the tumor and its microenvironment. The distinct methylome of CAFs provides a novel epigenetic hallmark of the cancer microenvironment and promises new biomarkers to improve interpretation of diagnostic samples.
Genome research. 2018 Apr 12 [Epub ahead of print]
Ruth Pidsley, Mitchell G Lawrence, Elena Zotenko, Birunthi Niranjan, Aaron Statham, Jenny Song, Roman M Chabanon, Wenjia Qu, Hong Wang, Michelle Richards, Shalima S Nair, Nicola J Armstrong, Hieu T Nim, Melissa Papargiris, Preetika Balanathan, Hugh French, Timothy Peters, Sam Norden, Andrew Ryan, John Pedersen, James Kench, Roger J Daly, Lisa G Horvath, Phillip Stricker, Mark Frydenberg, Renea A Taylor, Clare Stirzaker, Gail P Risbridger, Susan J Clark
Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia., Prostate Research Group, Cancer Program-Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash Partners Comprehensive Cancer Consortium, Monash University, Clayton, Victoria 3800, Australia., Tissupath Pathology, Mount Waverley, Victoria 3149, Australia., Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, New South Wales 2010, Australia., Signalling Network Laboratory, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash Partners Comprehensive Cancer Consortium, Monash University, Clayton, Victoria 3800, Australia., Prostate Cancer Translational Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.