Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptomic analysis of CAFs with silencing of ANKRD1.

ABSTRACT: Stromal cell senescence plays a crucial role in activating cancer-associated fibroblasts (CAFs). The Androgen receptor (AR) function oversees cellular senescence and CAF activation. Here, we identify the mesenchymal-specific transcriptional coregulator ANKRD1 as a key driver of CAF conversion. ANKRD1 is strongly upregulated in CAFs and under direct negative control of AR, and its loss impairs the pro-tumorigenic potential of CAFs. ANKRD1 controls a CAF-specific gene expression program and is associated with poorer survival of HNSCC, lung, and cervical SCC patients. Mechanistically, ANKRD1 binds to the chromatin on CAF gene regulatory regions in a complex with the AP1 transcription factor family. We show that ANKRD1 enhances the AP1 DNA binding activity to CAF gene promoters. Targeting ANKRD1 with the FANA antisense oligonucleotides reverts CAFs into a normal fibroblast, disrupts AP1 complex formation, and blocks CAF’s pro-tumorigenic potential in an orthotopic model of SCC, thus representing an exciting target for stroma-oriented cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218214 | GEO | 2023/11/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcriptomic analysis of human dermal fibroblasts overexpressing ANKRD1.

Project description:Stromal cell senescence plays a crucial role in activating cancer-associated fibroblasts (CAFs). The Androgen receptor (AR) function oversees cellular senescence and CAF activation. Here, we identify the mesenchymal-specific transcriptional coregulator ANKRD1 as a key driver of CAF conversion. ANKRD1 is strongly upregulated in CAFs and under direct negative control of AR, and its loss impairs the pro-tumorigenic potential of CAFs. ANKRD1 controls a CAF-specific gene expression program and is associated with poorer survival of HNSCC, lung, and cervical SCC patients. Mechanistically, ANKRD1 binds to the chromatin on CAF gene regulatory regions in a complex with the AP1 transcription factor family. We show that ANKRD1 enhances the AP1 DNA binding activity to CAF gene promoters. Targeting ANKRD1 with the FANA antisense oligonucleotides reverts CAFs into a normal fibroblast, disrupts AP1 complex formation, and blocks CAF’s pro-tumorigenic potential in an orthotopic model of SCC, thus representing an exciting target for stroma-oriented cancer therapy.

2023-11-10 | GSE218198 | GEO

ChIP-seq analysis of primary human dermal fibroblasts overexpressing ANKRD1 in human dermal fibroblasts (HDFs)

2023-11-10 | GSE218204 | GEO

Androgen receptor functions as transcriptional repressor of Cancer Associated Fibroblast (CAF) activation [ChIP-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 | GSE107320 | GEO

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

2018-08-28 | GSE107319 | GEO

STAT3 induces breast cancer growth and progression via IL-6, STC1 and MMP13 secretion by Cancer Associated Fibroblasts

Project description:In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6 act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among those, IL-6, ANGPTL4, STC-1 and MMP13 were validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. CAFs activities were moreover impaired by IL-6 Receptor blocking antibodies and by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The usefulness of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease.

2021-12-31 | GSE178081 | GEO

Genome wide analysis of skin cancer cell gene expresison exposed to stromal cancer associated fibroblasts in 3D gel matrix

Project description:SCC12 cells were seeded ontop of organotypic gels with HN-CAF (head and neck carcinoma associated fibroblasts). Differential gene expression was analysed between cancer cells not exposed to CAFs or non-invading cancer cells exposed to CAFs. Squamous cell cancer organotypics were constructed by embedding CAFs in collagen Matrigel matrix with SCC 12cells added on top. Gene expression was compared between non-invaded cancer cells and cancer cells not expoesd to CAFs.

2013-03-23 | E-GEOD-36776 | biostudies-arrayexpress

Estrogen Receptor Alpha Signaling in Cervical Cancer Associated Fibroblasts

Project description:Cancer Associated Fibroblasts (CAFs) are crucial in the genesis and progression of tumors. Cervical CAFs (C-CAFs) are less well characterized. Estrogen (E2) is considered a cofactor in cervical carcinogenesis. We studied the molecular signature of exvivo cultured C-CAFs from 4 early International Federation of Gynaecology and Obstetrics (FIGO, IB2) and 2 late (IIIA) stage disease using gene expression microarray. We found C-CAFs to be both pro-tumorigenic and moderately inflammatory; late stage C-CAFs were more actively metabolizing, and cycling, but expressed fewer genes related to immune function. We investigated the expression of ERα in exvivo cultured C-CAFs and studied the role of E2 in their biology by gene expression microarray in the presence of two ERα antagonists: ICI 182,780 and Methyl Piperidino Pyrazole (MPP). Both modulated C-CAF function by down regulating genes associated with cell cycle and metabolism, affecting angiogenesis and cancer progression, though their transcriptomes differed. MPP also down regulated genes involved in Epithelial to Mesenchymal Transition. Thus, canonical ERα signaling is vital for C-CAF functioning. Interfering with paracrine signaling through fibroblast ERα may be worth exploiting as a targeted therapy in cervical cancer. Gene expression microarray profiling of 4 early-stage E2 (estrogen) treated, 2 late-stage E2 treated, 2 early-stage ICI (ER-alpha antagonist) treated, 2 late-stage ICI treated and 2 early-stage MPP (ER-alpha antagonist) treated cervical cancer CAFs. E2 treated C-CAFs served as control.

2015-04-03 | E-GEOD-65227 | biostudies-arrayexpress

CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer [5920]

Project description:Cancer-associated fibroblasts (CAFs) are abundantly present in the microenvironment of virtually all tumors and strongly impact tumor progression. Despite increasing insight into their function and heterogeneity, little is known regarding the origin of CAFs. Understanding the origin of CAF heterogeneity is needed to develop successful CAF-based targeted therapies. Through various transplantation studies in mice we determined that CAFs in both invasive lobular breast cancer and triple negative breast cancer originate from mammary tissue-resident normal fibroblasts (NFs). Single-cell transcriptomics, in vivo tracing and in vitro studies revealed the transition of CD26+ and CD26- NF populations into inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs), respectively. In vitro functional assays showed that CD26+ NFs transition into pro-tumorigenic iCAFs which recruit myeloid cells in a CXCL12-dependent manner and enhance tumor cell invasion via matrix-metalloproteinase (MMP) activity. Together, our data show that CD26+ and CD26- NFs transform into distinct CAF subpopulations in breast cancer.

2022-11-29 | GSE205222 | GEO

CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer [4880_4954]

2022-11-29 | GSE205220 | GEO

CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer [6263_6381]

2022-11-29 | GSE214933 | GEO