Acquired anoikis resistance mediates enhancer-driven subtype plasticity in pancreatic cancer [ChIP-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA836436 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19142676.fastq.gz | Fastqsanger.gz | |||
| SRR19142677.fastq.gz | Fastqsanger.gz | |||
| SRR19142678.fastq.gz | Fastqsanger.gz | |||
| SRR19142679.fastq.gz | Fastqsanger.gz | |||
| SRR19142680.fastq.gz | Fastqsanger.gz |
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Project description:Acquired anoikis resistance mediates enhancer-driven subtype plasticity in pancreatic cancer [RNA-seq]
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Project description:Acquired anoikis resistance mediates enhancer-driven subtype plasticity in pancreatic cancer [ATAC-Seq]
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Project description:Genetic aberrations, including mutations or deletions in KRAS, TP53, SMAD4, and CDKN2A, are common causes of pancreatic ductal adenocarcinoma (PDA). Recent large-scale transcriptomic studies demonstrated that heterogeneous gene expressions played an essential role in determining molecular subtypes of PDA, although it remains unclear what the biological cues and consequences of distinct transcriptional programs are. Here, we describe an anoikis-induction-based experimental model that enforces the transition toward a squamous subtype of PDA cells. Characteristics of the squamous subtype, represented by aggressive behaviors, are faithfully recapitulated in vitro and in vivo, demonstrating the physiological relevance of this model. Integrated analysis of epigenome and transcriptome reveals that squamous subtype PDA cells acquire pro-angiogenic enhancer activity of which is sustained by the transcription factor TEAD2. Genetic and pharmacological inhibition of TEAD2 of these tumor cells impairs their pro-angiogenic phenotypes in vitro and cancer progression in vivo. Furthermore, we found that CD109 is a critical TEAD2 target that retains activated JAK-STAT signaling. Together, our findings implicate a TEAD2-CD109-JAK/STAT axis as a potential therapeutic vulnerability concealed in the squamous subtype-associated epigenome of pancreatic cancer cells.
2023-04-04 | GSE202532 | GEO
Project description:Genetic aberrations, including mutations or deletions in KRAS, TP53, SMAD4, and CDKN2A, are common causes of pancreatic ductal adenocarcinoma (PDA). Recent large-scale transcriptomic studies demonstrated that heterogeneous gene expressions played an essential role in determining molecular subtypes of PDA, although it remains unclear what the biological cues and consequences of distinct transcriptional programs are. Here, we describe an anoikis-induction-based experimental model that enforces the transition toward a squamous subtype of PDA cells. Characteristics of the squamous subtype, represented by aggressive behaviors, are faithfully recapitulated in vitro and in vivo, demonstrating the physiological relevance of this model. Integrated analysis of epigenome and transcriptome reveals that squamous subtype PDA cells acquire pro-angiogenic enhancer activity of which is sustained by the transcription factor TEAD2. Genetic and pharmacological inhibition of TEAD2 of these tumor cells impairs their pro-angiogenic phenotypes in vitro and cancer progression in vivo. Furthermore, we found that CD109 is a critical TEAD2 target that retains activated JAK-STAT signaling. Together, our findings implicate a TEAD2-CD109-JAK/STAT axis as a potential therapeutic vulnerability concealed in the squamous subtype-associated epigenome of pancreatic cancer cells.
2023-04-04 | GSE202527 | GEO
Project description:Genetic aberrations, including mutations or deletions in KRAS, TP53, SMAD4, and CDKN2A, are common causes of pancreatic ductal adenocarcinoma (PDA). Recent large-scale transcriptomic studies demonstrated that heterogeneous gene expressions played an essential role in determining molecular subtypes of PDA, although it remains unclear what the biological cues and consequences of distinct transcriptional programs are. Here, we describe an anoikis-induction-based experimental model that enforces the transition toward a squamous subtype of PDA cells. Characteristics of the squamous subtype, represented by aggressive behaviors, are faithfully recapitulated in vitro and in vivo, demonstrating the physiological relevance of this model. Integrated analysis of epigenome and transcriptome reveals that squamous subtype PDA cells acquire pro-angiogenic enhancer activity of which is sustained by the transcription factor TEAD2. Genetic and pharmacological inhibition of TEAD2 of these tumor cells impairs their pro-angiogenic phenotypes in vitro and cancer progression in vivo. Furthermore, we found that CD109 is a critical TEAD2 target that retains activated JAK-STAT signaling. Together, our findings implicate a TEAD2-CD109-JAK/STAT axis as a potential therapeutic vulnerability concealed in the squamous subtype-associated epigenome of pancreatic cancer cells.
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Project description:Anoikis resistance drives transcriptional plasticity in pancreatic cancer
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Project description:Anoikis resistance or evasion of cell death triggered by cell detachment is a hallmark of cancer that is concurrent with cell survival and metastasis. Phenotypes of anoikis resistant cancer cells have been extensively investigated, however, how exposure to suspension stress may lead to acquisition of a anoikis resistance phenotype has not been previously described in detail. Here we show using a spectrum of ovarian cancer cells, that cycles of suspension stress followed by attached growth, leads to adaptation and acquisition of resistance to cell death in suspension . Comparing the stepwise transcriptomic changes as cells acquire resistance, we find strong transcriptional reprogramming in the population with a majority of differentially expressed genes being downregulated during progressive acquisition of anoikis resistance. Adapted anoikis resistant cells display an enhanced dependency on oxidative phosphorylation and are capable of evasion from T cell-mediated immune surveillance. We find that such acquired anoikis resistance is not genetic. However, transcriptional reprogramming is essential to this process as acquisition of such adaptive anoikis resistance invitro and invivo are both exquisitely sensitive to specific inhibition of transcriptional reprogramming. Our data demonstrate that recovery from the verge of anoikis leads to adaptation that promotes metastasis in ovarian cancer, but can be therapeutically prevented by specific inhibitors to transcriptional reprogramming.
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Project description:Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTX inactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express both ASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in an active chromatin state with its loss increasing H3K27me3 near their promoters leading to a cell state that is primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides a novel autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs
2023-06-08 | GSE211242 | GEO
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Project description:Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1,POU2F3, and Inflammatory. Initially SCLC subtypes were thought to be mutually exclusive, butrecent evidence shows intra-tumoral subtype heterogeneity and plasticity between subtypes.Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTXinactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express bothASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in anactive chromatin state with its loss increasing H3K27me3 near their promoters leading to a cell state that is primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as \an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides a novel autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.
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