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Physical and functional CSL-p53 interactions underlie control of cancer stromal cell evolution [ChIP-seq]

ABSTRACT: Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-Jκ in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control.

ORGANISM(S): Homo sapiens

PROVIDER: GSE59942 | GEO | 2015/08/24

SECONDARY ACCESSION(S): PRJNA257105

REPOSITORIES: GEO

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Physical and functional CSL-p53 interactions underlie control of cancer stromal cell evolution [RNA-seq]

Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-Jκ in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. Human Dermal Fibroblasts were transfected with two different siRNA against CSL in parallel with a control siRNA. Total RNA was extracted 3 days post-transfection, followed by RNA-Seq analysis.

2015-08-24 | E-GEOD-65473 | biostudies-arrayexpress

Physical and functional CSL-p53 interactions underlie control of cancer stromal cell evolution [RNA-seq]

2015-08-24 | GSE65473 | GEO

Physical and functional CSL-p53 interactions underlie control of cancer stromal cell evolution [ChIP-seq]

Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-J? in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. Examination of genome-wide CSL binding sites in primary human dermal fibroblasts usinf two different antibodies against CSL

2015-08-24 | E-GEOD-59942 | biostudies-arrayexpress

Global changes in gene expression in human dermal fibroblasts after CSL silencing

Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-J-kappa in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, with p53 activation providing a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblasts senescence, enhances CAF effector gene expression and, in vivo, promotes stromal and cancer cell expansion. Together, these findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. We used microarrays to detail the global changes in gene expression in human dermal fibroblasts after CSL silencing

2017-12-04 | GSE59847 | GEO

Androgen receptor functions as transcriptional repressor of Cancer Associated Fibroblast (CAF) activation [RNA-seq]

Project description:The age-associated increase of cancer risk has been linked with stromal fibroblast senescence and early steps of Cancer Associated Fibroblast (CAF) activation. Surprisingly little is known about the role of androgen receptor (AR) signalling in this context. We show that AR expression is down-modulated in stromal fibroblasts underlying premalignant skin cancer lesions (actinic keratoses, AK) as well as in CAFs from the three major skin cancer types, squamous (SCC) and basal cell (BCC) carcinomas and melanomas. Decreased AR expression is linked to the concomitant down-modulation of CSL, key effector of canonical Notch signalling and global modulator of chromatin configuration, and it can be counteracted by treatment with BET inhibitors, which reverse CAF activation. Functionally, AR gene silencing in dermal fibroblasts results in p53-dependent senescence and induction of key CAF-effector genes, with AR physically converging with CSL in negative control of these genes. The findings are of functional significance as, in an orthotopic model of skin cancer, dermal fibroblasts with AR loss enhance significantly tumorigenicity of SCC and melanoma cells. As such, the findings establish AR as a novel potential target for stroma-focused cancer prevention and treatment.

2018-08-28 | GSE107319 | GEO

Androgen receptor functions as transcriptional repressor of Cancer Associated Fibroblast (CAF) activation [ChIP-seq]

2018-08-28 | GSE107320 | GEO

Convergent roles of ATF3 and CSL in chromatin control of CAF activation [RNA-seq]

Project description:Cancer associated fibroblasts (CAFs) play an important role in initiating and promoting epithelial cancers. The specific chromatin modifications involved in CAF activation remain to be elucidated. CSL, a constitutive transcriptional repressor and mediator of canonical Notch signaling, functions as a direct negative regulator of CAF effector genes and suppresses cancer/stromal cell expansion. We find that ATF3, a key stress responsive transcriptional repressor up-regulated in the acute UVA response of skin fibroblasts, is down-modulated in stromal cells of premalignant skin SCC lesions similarly to CSL. Increased ATF3 expression counteracts the consequences of compromised CSL, binding to a large set of overlapping target genes. At low basal levels, ATF3 converges with CSL in negative control of CAF activation, binding to a very small number of genomic loci that encompass mostly non-coding RNAs and pseudogenes. Silencing of ATF3 results in chromatin modifications and Pol II recruitment to many loci to which ATF3 does not bind, which are similarly affected by CSL silencing. The observed changes are of functional significance, as Bet inhibitors, which unlink activated chromatin from the basic transcription apparatus, have opposite effects of ATF3 or CSL silencing on all tested CAF effector genes. They exert a similar impact on clinically-derived CAFs both in vitro and upon topical in vivo treatment. Thus, ATF3 converges with CSL in global chromatin control of CAF activation with their loss eliciting epigenetic changes amenable to cancer and stroma-focused intervention.

2017-06-30 | GSE81405 | GEO

Convergent roles of ATF3 and CSL in chromatin control of CAF activation [HistoneMarkers ChIPseq]

2017-06-30 | GSE81404 | GEO

Convergent roles of ATF3 and CSL in chromatin control of CAF activation [ATF3 ChIP-seq]

2017-06-30 | GSE81403 | GEO

Dual role of CSL (RBP-Jk) and NOTCH1 in cancer-associated fibroblast genome stability and expansion [RNA-seq]

Project description:Genomic instability is a hallmark of cancer. Whether or not it also occurs in cancer-associated fibroblasts (CAFs) is a question of importance for the cancer/stromal cell co-evolution process. We find that DNA damage, telomere shortening and chromosome fusions occur at early times of CAF activation, as triggered by silencing of the CSL/RBP-J-κ gene in primary human dermal fibroblasts (HDFs) from multiple individuals. Similar alterations occur in skin Squamous Cell Carcinoma (SCC) - derived CAFs, in which CSL is down-modulated, versus HDFs from unaffected skin of the same patients. Mechanistically, CSL is part of a telomere protective complex with UPF1, KU70, and KU80 proteins, which fail to bind to telomeres in the absence of CSL. In CAFs, persistent genomic instability is associated with frequent amplification and overexpression of NOTCH1 gene, which is required to suppress DNA damage-induced ATM/P53 activation and growth arrest. These findings are of translational significance as, in an orthotopic model of skin SCC, genetic or pharmacological suppression of NOTCH1 activity suppresses cancer/stromal cell proliferation and expansion.

2019-09-11 | GSE113542 | GEO

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