Alterations in the methylome of the stromal tumour microenvironment signal the presence and severity of prostate cancer

Abstract

Background: Prostate cancer changes the phenotype of cells within the stromal microenvironment, including fibroblasts, which in turn promote tumour progression. Functional changes in prostate cancer-associated fibroblasts (CAFs) coincide with alterations in DNA methylation levels at loci-specific regulatory regions. Yet, it is not clear how these methylation changes compare across CAFs from different patients. Therefore, we examined the consistency and prognostic significance of genome-wide DNA methylation profiles between CAFs from patients with different grades of primary prostate cancer. Results: We used Infinium MethylationEPIC BeadChips to evaluate genome-wide DNA methylation profiles from 18 matched CAFs and non-malignant prostate tissue fibroblasts (NPFs) from men with moderate to high grade prostate cancer, as well as five unmatched benign prostate tissue fibroblasts (BPFs) from men with benign prostatic hyperplasia. We identified two sets of differentially methylated regions (DMRs) in patient CAFs. One set of DMRs reproducibly differed between CAFs and fibroblasts from non-malignant tissue (NPFs and BPFs). Indeed, more than 1200 DMRs consistently changed in CAFs from every patient, regardless of tumour grade. The second set of DMRs varied between CAFs according to the severity of the tumour. Notably, hypomethylation of the EDARADD promoter occurred specifically in CAFs from highgrade tumours and correlated with increased transcript abundance and increased EDARADD staining in patient tissue. Across multiple cohorts, tumours with low EDARADD DNA methylation and high EDARADD mRNA expression were consistently associated with adverse clinical features and shorter recurrence free survival.

DNA Methylation Profiling of Human Hepatocarcinogenesis

“…In prostate cancer, the DNA methylome of the tumor microenvironment was found to correlate with the presence and severity of cancer. ( 52 ) In colorectal cancer, aberrant DNA methylation of healthy mucosa correlates with cancer development, ( 51 ) and hypermethylation of specific genes in the healthy colonic mucosa is predictive of survival. ( 53 ) Similarly, our results suggest that the DNA methylation profile of the cirrhotic tumor‐adjacent tissue is a predictor of survival in HCC.…”

Cancer-associated fibroblasts of the prostate promote a compliant and more invasive phenotype in benign prostate epithelial cells

“…1 A and B) [ 36 ]. CAFs and NPFs from both patient-matched pairs exhibit distinct epigenome profiles [ 41 ] and show functional differences in vitro [ 17 ]. The fibroblasts were grown to confluency and induced for matrix secretion with ascorbic acid for 5 days.…”

“…In this study, we compared the mechanical properties of primary CAFs and non-malignant prostate tissue fibroblasts (NPFs) isolated from malignant or benign regions of prostate tissue from the same patient [ 36 ]. Previous works have identified distinct proteomic and epigenetic profiles in patient-matched pairs of stromal cells, altered interactions with epithelial and immune cells, as well as aberrant ECM deposition, compared with normal fibroblasts from the prostate [ 17 , [37] , [38] , [39] , [40] , [41] ]. Here, we compare the mechanical characteristics of patient-matched CAFs and NPFs as well as their co-cultures with benign prostatic epithelial cells using AFM and RT-FDC.…”

Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment

“…Cancer-associated fibroblasts (CAFs) are present in the early stages of tumorigenesis and differ from their non-malignant prostate fibroblast (NPF) counterparts at the transcriptomic [ 8 ], epigenomic [ 9 , 10 ], and proteomic level [ 11 ]. Functional assessment of primary prostate fibroblast populations reveals that CAFs retain the ability to initiate and potentiate tumorigenicity in adjacent prostate epithelia [ 12 , 13 , 14 , 15 , 16 ].…”