Author:
Pidsley Ruth,Lawrence Mitchell G.,Zotenko Elena,Niranjan Birunthi,Statham Aaron,Song Jenny,Chabanon Roman M.,Qu Wenjia,Wang Hong,Richards Michelle,Nair Shalima S.,Armstrong Nicola J.,Nim Hieu T.,Papargiris Melissa,Balanathan Preetika,French Hugh,Peters Timothy,Norden Sam,Ryan Andrew,Pedersen John,Kench James,Daly Roger J.,Horvath Lisa G.,Stricker Phillip,Frydenberg Mark,Taylor Renea A.,Stirzaker Clare,Risbridger Gail P.,Clark Susan J.
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.
Funder
Cancer Australia
National Health and Medical Research Council
Cancer Institute of New South Wales
Australian Prostate Cancer Research Centre-NSW
Prostate Cancer Foundation of Australia
Movember Young Investigator
Victorian Cancer Agency
RT Hall Trust
TissuPath Pathology
Publisher
Cold Spring Harbor Laboratory
Subject
Genetics (clinical),Genetics