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Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE144388 | GEO | 2021/03/16

REPOSITORIES: GEO

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Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy.

Project description:Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC.

| S-EPMC8034383 | biostudies-literature

Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy [scRNA-Seq]

Project description:Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified ARID1A, a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, our mouse genetic and single cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage dependent roles. Utilizing this unique vulnerability of Arid1a mutated GC cells, our combinatorial treatment with an epigenetic inhibitor and a p53 agonist selectively inhibited Arid1a heterozygous tumor growth, providing a novel therapeutic option for GC.

2021-03-16 | GSE144387 | GEO

Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy [RNA-Seq]

2021-03-16 | GSE144386 | GEO

Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy [ChIP-Seq]

2021-03-16 | GSE144385 | GEO

Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy

Project description:Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy

| PRJNA603539 | ENA

Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy [RNA-Seq]

Project description:Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy [RNA-Seq]

| PRJNA603540 | ENA

Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy [ChIP-Seq]

Project description:Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy [ChIP-Seq]

| PRJNA603541 | ENA

Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy [scRNA-Seq]

Project description:Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy [scRNA-Seq]

| PRJNA603542 | ENA

Context-Dependent Roles of Claudins in Tumorigenesis.

Project description:The barrier and fence functions of the claudin protein family are fundamental to tissue integrity and human health. Increasing evidence has linked claudins to signal transduction and tumorigenesis. The expression of claudins is frequently dysregulated in the context of neoplastic transformation. Studies have uncovered that claudins engage in nearly all aspects of tumor biology and steps of tumor development, suggesting their promise as targets for treatment or biomarkers for diagnosis and prognosis. However, claudins can be either tumor promoters or tumor suppressors depending on the context, which emphasizes the importance of taking various factors, including organ type, environmental context and genetic confounders, into account when studying the biological functions and targeting of claudins in cancer. This review discusses the complicated roles and intrinsic and extrinsic determinants of the context-specific effects of claudins in cancer.

| S-EPMC8329526 | biostudies-literature

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis.

Project description:TP53 and ARID1A are frequently mutated across cancer but rarely in the same primary tumor. Endometrial cancer has the highest TP53-ARID1A mutual exclusivity rate. However, the functional relationship between TP53 and ARID1A mutations in the endometrium has not been elucidated. We used genetically engineered mice and in vivo genomic approaches to discern both unique and overlapping roles of TP53 and ARID1A in the endometrium. TP53 loss with oncogenic PIK3CAH1047R in the endometrial epithelium results in features of endometrial hyperplasia, adenocarcinoma, and intraepithelial carcinoma. Mutant endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A/PIK3CA mutant endometrium. In the context of either TP53 or ARID1A loss, PIK3CA mutant endometrium exhibited inflammatory pathway activation, but other gene expression programs differed based on TP53 or ARID1A status, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with each respective genetic alteration. Consistent with TP53-ARID1A mutual exclusivity, the p53 pathway is activated following ARID1A loss in the endometrial epithelium, where ARID1A normally directly represses p53 pathway genes in vivo, including the stress-inducible transcription factor, ATF3. However, co-existing TP53-ARID1A mutations led to invasive adenocarcinoma associated with mutant ARID1A-driven ATF3 induction, reduced apoptosis, TP63+ squamous differentiation and invasion. These data suggest TP53 and ARID1A mutations drive shared and distinct tumorigenic programs in the endometrium and promote invasive endometrial cancer when existing simultaneously. Hence, TP53 and ARID1A mutations may co-occur in a subset of aggressive or metastatic endometrial cancers, with ARID1A loss promoting squamous differentiation and the acquisition of invasive properties.

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