Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

Nash, Christopher; Boufaied, Nadia; Mills, Ian G.; Franco, Omar E.; Hayward, Simon W.; Thomson, Axel A.

doi:10.1016/j.mce.2017.05.006

Cited by 31 publications

(36 citation statements)

References 69 publications

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“…We observed that CM of testosterone‐stimulated CAF‐like cells reduced migration of PCa cells, while antiandrogens restored tumor cell migration. As previously described in CAFs, we also observed AR binding in functional enhancer regions that are marked by the H3K27Ac acetylation mark and very limited overlap of AR sites was observed between fibroblasts, prostate tumors, and LNCaP (Nash et al ., ; Nevedomskaya et al ., ). We confirmed previous data showing that AR binding in human prostate CAFs might not only be dependent on the classic AR pioneer transcription factors such as FOXA, but rather act via the AP1 complex (Leach et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Loss of androgen receptor signaling in prostate cancer‐associated fibroblasts (CAFs) promotes CCL2‐ and CXCL8‐mediated cancer cell migration

et al. 2018

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Fibroblasts are abundantly present in the prostate tumor microenvironment (TME), including cancer‐associated fibroblasts (CAFs) which play a key role in cancer development. Androgen receptor (AR) signaling is the main driver of prostate cancer (PCa) progression, and stromal cells in the TME also express AR. High‐grade tumor and poor clinical outcome are associated with low AR expression in the TME, which suggests a protective role of AR signaling in the stroma against PCa development. However, the mechanism of this relation is not clear. In this study, we isolated AR‐expressing CAF‐like cells. Testosterone (R1881) exposure did not affect CAF‐like cell morphology, proliferation, or motility. PCa cell growth was not affected by culturing in medium from R1881‐exposed CAF‐like cells; however, migration of PCa cells was inhibited. AR chromatin immune precipitation sequencing (ChIP‐seq) was performed and motif search suggested that AR in CAF‐like cells bound the chromatin through AP‐1‐elements upon R1881 exposure, inducing enhancer‐mediated AR chromatin interactions. The vast majority of chromatin binding sites in CAF‐like cells were unique and not shared with AR sites observed in PCa cell lines or tumors. AR signaling in CAF‐like cells decreased expression of multiple cytokines; most notably CCL2 and CXCL8 and both cytokines increased migration of PCa cells. These results suggest direct paracrine regulation of PCa cell migration by CAFs through AR signaling.

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Section: Discussionmentioning

confidence: 99%

Loss of androgen receptor signaling in prostate cancer‐associated fibroblasts (CAFs) promotes CCL2‐ and CXCL8‐mediated cancer cell migration

et al. 2018

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“…et al 2017; Nash et al 2017). Many of the CAF-associated DMRs also create ectopic enhancer (LMRs) and promoter (UMRs) elements, and more than a third extend preexisting LMRs or UMRs, indicating a cancer-associated spread of hyper-or hypomethylation at the border of these regulatory elements.…”

Section: Discussionmentioning

confidence: 99%

Enduring epigenetic landmarks define the cancer microenvironment

et al. 2018

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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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“…Using next generation RNASeq, MACS based human and mouse cell sorting, mass spectrometry and organism-specific reference databases we have identified the tumor-specific (human) from the stroma-specific (mouse) transcriptome and proteome of bone metastasis PCa PDXs. The dynamics of AR signalling in the stroma are best represented in an in vivo setting [27], therefore to specifically examine the stroma changes dictated by PCa cells, we subjected the PDXs in androgen and androgen-deprived conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Stromal cells do express Androgen Receptor (AR) and have active downstream signaling, while absence of stromal AR expression is used as a prognostic factor of disease progression [9]. Furthermore, AR binds to different genomic sites in prostate fibroblasts compared to epithelium [10] and to cancer associated fibroblasts (CAFs) [11], indicating different roles of AR in epithelial or stroma cellular contexts. Prostate CAFs have tumor promoting effects on marginally tumorigenic cells (LNCaP), irreversibly alter their phenotype and influence progression to androgen independence and metastasis [12,13].…”

Section: Introductionmentioning

confidence: 99%

Stroma transcriptomic and proteomic profile of prostate cancer metastasis xenograft models reveals conservation of bone microenvironment signatures

Karkampouna

Filippo

et al. 2020

Preprint

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Prostate cancer (PCa) is the second leading cause of cancer-associated death in men with therapy resistance acquisition to androgen deprivation treatment and metastasis progression.Understanding the mechanisms of tumor progression to metastatic stage is necessary for the design of therapeutic and prognostic schemes. The main objective of the current study is to determine, using transcriptomic and proteomic analyses on patient derived-xenograft models, whether differentially aggressive PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern, and how this information could be applied in prognostics.Transcriptomic profiling (RNA Sequencing) was performed on PCa PDX models representing different disease stages; BM18 (androgen dependent bone metastasis) and LAPC9 (androgen independent bone metastasis). Using organism-specific reference databases, the humanspecific transcriptome, representing the tumor, was identified and separated from the mousespecific transcriptome (representing the contributing stroma counterpart) from the same PDX tumor samples. To identify proteome changes in the tumor (human) versus the stroma (mouse), we performed human and mouse cell separation using the MACS mouse depletion sorting kit, and subjected protein lysates to quantitative TMT labeling and mass spectrometry. We show

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Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

Cited by 31 publications

References 69 publications

Loss of androgen receptor signaling in prostate cancer‐associated fibroblasts (CAFs) promotes CCL2‐ and CXCL8‐mediated cancer cell migration

Loss of androgen receptor signaling in prostate cancer‐associated fibroblasts (CAFs) promotes CCL2‐ and CXCL8‐mediated cancer cell migration

Enduring epigenetic landmarks define the cancer microenvironment

Stroma transcriptomic and proteomic profile of prostate cancer metastasis xenograft models reveals conservation of bone microenvironment signatures

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