Enduring epigenetic landmarks define the cancer microenvironment

Pidsley, Ruth; Lawrence, Mitchell G.; Zotenko, Elena; Niranjan, Birunthi; Statham, Aaron L.; Song, Jenny Z.; Chabanon, R; Qu, Wenjia; Wang, Hong; Richards, Michelle; Nair, Shalima S.; Armstrong, Nicola J.; Nim, Hieu T.; Papargiris, Melissa; Balanathan, Preetika; French, Hugh J.; Peters, Timothy J.; Norden, Sam; Ryan, Andrew; Pedersen, John; Kench, James G.; Daly, Roger J.; Horvath, Lisa G.; Stricker, Phillip D.; Frydenberg, Mark; Taylor, Renea A.; Stirzaker, Clare; Risbridger, Gail P.; Clark, Susan J.

doi:10.1101/gr.229070.117

Cited by 75 publications

(90 citation statements)

References 52 publications

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“…In addition to genetic factors, alterations in epigenetic regulation contribute significantly to the initiation and progression of cancer [40,41]. Epigenetic pathways are also implicated in the observed intratumor heterogeneity [40] and alterations in the tumor microenvironment [42].…”

Section: Discussionmentioning

confidence: 99%

A multicenter analysis of genomic profiles and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the lung

et al. 2020

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To understand the molecular mechanism of tumorigenesis of pulmonary lymphoepithelioma-like carcinoma and explore potential therapeutic strategies, we investigated the genomic profiles and PD-L1 expression of 29 Chinese pulmonary lymphoepithelioma-like carcinoma patients at various stages. We performed capture-based targeted sequencing on tissue samples collected from 27 patients with sufficient samples using a panel consisting of 520 cancer-related genes, spanning 1.64 Mb of the human genome. We identified 184 somatic mutations in 109 genes from 26 patients. One patient had no mutations detected by this panel. Copy number variations were detected in 52% (14/27) of the patients, with a majority having advancedstage disease (10/14). Except for the detection of ERBB2 amplification and KRAS mutation in two patients, no other classic lung cancer driver mutations were detected. Interestingly, 78% (21/27) of the patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in 29 epigenetics-related genes. Furthermore, we performed PD-L1 immunohistochemistry staining using the Dako 22C3 assay and demonstrated that 69% (20/29) of the cohort had positive PD-L1 expression, of which three patients received and benefited from a PD-1 inhibitor. In conclusion, we elucidated a distinct genomic landscape associated with pulmonary lymphoepithelioma-like carcinoma with no classic lung cancer driver mutation but an enrichment of mutations in epigenetic regulators. The detection of high PD-L1 expression and lack of any canonical druggable driver mutations raises the potential of checkpoint immunotherapy for pulmonary lymphoepithelioma-like carcinoma.

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Section: Discussionmentioning

confidence: 99%

A multicenter analysis of genomic profiles and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the lung

et al. 2020

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“…This stable phenotype is not due to genomic aberrations [24,25]. Rather, we recently showed that CAFs harbour DNA methylation alterations compared to non-malignant prostate tissue fibroblasts (NPFs), particularly enriched at regulatory regions of the genome [24]. Other studies have also identified differential methylation of candidate genes and an altered repertoire of transcription factor binding sites in CAFs [6,26,27].…”

Section: Introductionmentioning

confidence: 88%

“…This is demonstrated by primary cultures of patient-derived CAFs, which retain distinctive transcriptomic and proteomic profiles and ability to promote tumour progression, even when cultured without tumour epithelium [8,10,22,23]. This stable phenotype is not due to genomic aberrations [24,25]. Rather, we recently showed that CAFs harbour DNA methylation alterations compared to non-malignant prostate tissue fibroblasts (NPFs), particularly enriched at regulatory regions of the genome [24].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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“…While genetic aberrations, such as mutations or chromosomal rearrangements, are rare in CAFs [54,55], they can be epigenetically altered upon interactions with neighbouring cells via DNA and Figure 1C) [56,57]. Methylation is a reversible process that can be targeted with demethylating drugs, such as 5-aza-2'-deoxycytidine (DAC).…”

Section: Caf Heterogeneity At the Epigenetic Levelmentioning

confidence: 99%

CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer

et al. 2019

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Cancer-associated fibroblasts (CAFs) are one of the most significant components in the tumour microenvironment (TME), where they can perform several protumourigenic functions. Several studies have recently reported that CAFs are more heterogenous and plastic than was previously thought. As such, there has been a shift in the field to study CAF subpopulations and the emergent functions of these subsets in tumourigenesis. In this review, we explore how different aspects of CAF heterogeneity are defined and how these manifest in multiple cancers, with a focus on pancreatic ductal adenocarcinoma (PDAC). We also discuss therapeutic approaches to selectively target protumourigenic CAF functions, while avoiding normal fibroblasts, providing insight into the future of stromal targeting for the treatment of PDAC and other solid tumours. Cancer-Associated Fibroblasts: Major Players in Pancreatic Tumourigenesis PDAC is one of the most lethal solid malignancies, with a 5-year survival rate of $9% [1]. Widespread fibrotic desmoplasia is one of the cornerstones of PDAC development, progression, metastasis, and treatment resistance, where stromal components of the TME can have fundamental and integrated roles in promoting tumourigenesis [2-6]. This extensive desmoplastic reaction is characterised by the recruitment and activation of CAFs, aberrant extracellular matrix (ECM) deposition and remodelling, tumour angiogenesis, altered blood supply, as well as increased inflammation coupled with altered (and often impaired) innate and adaptive immune responses [4,5,7-9]. CAFs are one of the most prominent and active components in the pancreatic TME [4,5]. During early tumour initiation, reciprocal tumour-stroma signalling drives the reprogramming of mesenchymal cells, such as pancreatic stellate cells (PSCs), into CAFs [6], after which they can perform numerous anti-and protumourigenic functions in the TME. For instance, PDAC CAFs are the chief source of fibrotic matrisomal components, such as collagens, hyaluronic acid (HA), and fibronectin, among others, as recently described by Tian et al. [10]. This fibrosis has downstream biomechanical and biochemical effects in the TME [11], including impaired drug efficacy due to reduced interfibrillar spacing in the interstitium, which leads to reduced vascular patency and poor immune cell infiltration [12-17]. Moreover, CAFs produce several chemokines, cytokines, growth factors, miRNAs, exosomes, and metabolites that can instruct cancer cells and other TME components to promote malignant biology [4,5]. Given the central role of CAFs in the TME, there have been several attempts to target them in combination with other therapeutic approaches, such as chemotherapy or immunotherapy, for the treatment of PDAC. Thus far, this treatment approach has been largely unsuccessful and, in some preclinical studies, harmful. This is best exemplified through the studies of Ö zdemir et al. [18] and Rhim et al. [19], which both found that depletion of CAFs in genetically engineered mouse models (GEMMs) of PDA...

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Enduring epigenetic landmarks define the cancer microenvironment

Cited by 75 publications

References 52 publications

A multicenter analysis of genomic profiles and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the lung

A multicenter analysis of genomic profiles and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the lung

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

CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer

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