Transcriptomic analysis of CAFs with silencing of ANKRD1.
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ABSTRACT:
PROVIDER: PRJNA902760 | ENA |
REPOSITORIES: ENA
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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 | GSE218214 | GEO
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
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.
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Project description:Transcriptomic analysis of human dermal fibroblasts overexpressing ANKRD1.
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Project description:Cellular senescence is a complex biological process that contributes to wound healing, carcinogenesis, and age-related disease. Although the molecular mechanisms whereby senescence promotes wound repair are not well understood, the protein ANKRD1, which promoted wound healing in mice, was found to increase in senescent cells. We hypothesized that ANKRD1 may play a role in senescence-mediated wound healing. Conditioned medium (CM) from senescent WI-38 human diploid fibroblasts hastened cell migration of human HaCaT keratinocytes. Interestingly, silencing ANKRD1 in WI-38 cells reduced the effect of CM on cell migration, while overexpressing ANKRD1 accelerated it. Further proteomic analysis revealed that ANKRD1 associates with YBOX1, a multifunctional protein that modulates transcription of the ELN gene and reduces ELN mRNA production. The product of the ELN gene, the protein ELN or tropoelastin (a subunit of elastin), is a secreted factor that reduces motility. Thus, we propose that a rise in ANKRD1 during early senescence transiently limits the YBOX1-dependent transcriptional increase in ELN production, and thereby enables cell motility in early phases of senescence.
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Project description:The pancreatic cancer tumor microenvironment is dominated primarily by cancer-associated fibroblasts (CAFs) and tumor associated macrophages (TAMs). The interecellular dialogue between CAFs and TAMs and the resulting impact on chemoresistance, specifically to Folfirinox, remains poorly understood. In this study, we sought to understand the impact of primary PDAC CAFs on macrophage reprogramming in a folfirinox-dependent manner and performed various cellular assays (viability, immunophenotyping, phagocytosis, secretory profile analysis) and transcriptomic analysis.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer associated fibroblasts (CAFs). CAFs promote tumor growth, metastasis and treatment resistance. We aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAFs) were generated by continuous incubation in 100nM gemcitabine. Gene expression differences between treatment naïve CAFs (N-CAFs) and R-CAFs were compared by array analysis.
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