Altered p53 functionality in cancer-associated fibroblasts contributes to their cancer-supporting features

Arandkar, Sharathchandra; Furth, Noa; Elisha, Yair; Nataraj, Nishanth Belugali; Kuip, Heiko van der; Aulitzky, Walter E.; Ulitsky, Igor; Geiger, Benjamin; Oren, Moshe

doi:10.1073/pnas.1719076115

Cited by 89 publications

(86 citation statements)

References 56 publications

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“…S3). These results mirror an emerging role for p53 in inflammatory gene regulation in macrophages (42) and fibroblasts (43). Depending on the degree and context in which p53 drives these inflammatory signaling this may position p53 as a regulator of inflammatory signaling in epithelial systems including many cancers.…”

Section: Discussionsupporting

confidence: 53%

Identification of universal and cell type specific p53 DNA binding

Hafner

Kublo

Lahav

et al. 2017

Preprint

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The tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind and activate cell type specific gene expression programs, however recent studies and meta-analyses of genomic data propose largely uniform, and condition independent, p53 binding. To systematically assess the cell type specificity of p53, we measured its association with DNA in 12 p53 wildtype cell lines, from a range of epithelial linages, in response to ionizing radiation. We found that the majority of bound sites were occupied across all cell lines, however we also identified a subset of binding sites that were specific to one or a few cell lines. Unlike the shared p53-bound genome, which was not dependent on chromatin accessibility, the association of p53 with these atypical binding sites was well explained by chromatin accessibility and could be modulated by forcing cell state changes such as the epithelial-to-mesenchymal transition. These results position p53 as having both universal and cell type specific regulatory programs that have different regulators and dependence on chromatin state.

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Section: Discussionsupporting

confidence: 53%

Identification of universal and cell type specific p53 DNA binding

Hafner

Kublo

Lahav

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

“…5, Additional file 4: Figure S6). These results mirror an emerging role for p53 in inflammatory gene regulation in macrophages [34] and fibroblasts [35]. Depending on the degree and context in which p53 drives these inflammatory signaling, this may position p53 as a regulator of inflammatory signaling in epithelial systems including many cancers.…”

Section: Discussionsupporting

confidence: 52%

Identification of universal and cell-type specific p53 DNA binding

Hafner

Kublo

Tsabar

et al. 2020

BMC Mol and Cell Biol

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Background: The tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind and activate cell-type specific gene expression programs. However recent studies and meta-analyses of genomic data propose largely uniform, and condition independent p53 binding and thus question the selective and cell-type dependent function of p53. Results: To systematically assess the cell-type specificity of p53, we measured its association with DNA in 12 p53 wild-type cancer cell lines, from a range of epithelial linages, in response to ionizing radiation. We found that the majority of bound sites were occupied across all cell lines, however we also identified a subset of binding sites that were specific to one or a few cell lines. Unlike the shared p53-bound genome, which was not dependent on chromatin accessibility, the association of p53 with these atypical binding sites was well explained by chromatin accessibility and could be modulated by forcing cell state changes such as the epithelial-to-mesenchymal transition. Conclusions: Our study reconciles previous conflicting views in the p53 field, by demonstrating that although the majority of p53 DNA binding is conserved across cell types, there is a small set of cell line specific binding sites that depend on cell state.

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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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Altered p53 functionality in cancer-associated fibroblasts contributes to their cancer-supporting features

Cited by 89 publications

References 56 publications

Identification of universal and cell type specific p53 DNA binding

Identification of universal and cell type specific p53 DNA binding

Identification of universal and cell-type specific p53 DNA binding

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

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