Enduring epigenetic landmarks define the cancer microenvironment
- Ruth Pidsley1,2,17,
- Mitchell G. Lawrence3,4,17,
- Elena Zotenko1,2,
- Birunthi Niranjan3,
- Aaron Statham1,
- Jenny Song1,
- Roman M. Chabanon1,
- Wenjia Qu1,
- Hong Wang3,
- Michelle Richards3,
- Shalima S. Nair1,2,
- Nicola J. Armstrong1,5,
- Hieu T. Nim3,6,7,
- Melissa Papargiris3,
- Preetika Balanathan3,
- Hugh French1,
- Timothy Peters1,
- Sam Norden8,
- Andrew Ryan8,
- John Pedersen3,8,
- James Kench9,10,
- Roger J. Daly11,
- Lisa G. Horvath9,12,13,
- Phillip Stricker9,14,
- Mark Frydenberg3,
- Renea A. Taylor4,15,
- Clare Stirzaker1,2,
- Gail P. Risbridger3,4,16,17 and
- Susan J. Clark1,2,17
- 1Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia;
- 2St. Vincent's Clinical School, UNSW Sydney, New South Wales 2052, Australia;
- 3Prostate Research Group, Cancer Program—Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash Partners Comprehensive Cancer Consortium, Monash University, Clayton, Victoria 3800, Australia;
- 4Prostate Cancer Translational Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia;
- 5Mathematics and Statistics, Murdoch University, Perth, Western Australia 6150, Australia;
- 6Faculty of Information Technology, Monash University, Clayton, Victoria 3800, Australia;
- 7Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia;
- 8Tissupath Pathology, Mount Waverley, Victoria 3149, Australia;
- 9Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, New South Wales 2010, Australia;
- 10Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia;
- 11Signalling Network Laboratory, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash Partners Comprehensive Cancer Consortium, Monash University, Clayton, Victoria 3800, Australia;
- 12Chris O'Brien Lifehouse, Missenden Road, Camperdown, New South Wales 2050, Australia;
- 13University of Sydney, Sydney, New South Wales 2050, Australia;
- 14Department of Urology, St. Vincent's Prostate Cancer Centre, Sydney, New South Wales 2050, Australia;
- 15Prostate Research Group, Cancer Program—Biomedicine Discovery Institute Department of Physiology, Monash Partners Comprehensive Cancer Consortium, Monash University, Clayton, Melbourne, Victoria 3800, Australia;
- 16Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria 3010, Australia
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↵17 These authors contributed equally to this work.
Abstract
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.229070.117.
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Freely available online through the Genome Research Open Access option.
- Received August 14, 2017.
- Accepted March 27, 2018.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
