Research

Enduring epigenetic landmarks define the cancer microenvironment

    • 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
    • 17 These authors contributed equally to this work.
Published April 12, 2018. https://doi.org/10.1101/gr.229070.117
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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.

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