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Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [RNA-Seq]

ABSTRACT: Lineage plasticity has been proposed as a major source of intratumoral heterogeneity and therapeutic resistance. Employing an inducible genetic engineered mouse model, we illustrate that lineage plasticity enables advanced Pancreatic Ductal Adenocarcinoma (PDAC) tumors to develop spontaneous relapse following elimination of the central oncogenic driver - Yap. Transcriptomic and immunohistochemistry analysis of a large panel of PDAC tumors reveals that within high-grade tumors, small niches of PDAC cells gradually evolve to re-activate pluripotent transcription factors (PTFs), which lessen their dependency on Yap. Comprehensive Cut&Tag analysis demonstrate that although acquisition of PTF expression is coupled with the process of epithelial-to-mesenchymal transition (EMT), PTFs form a core transcriptional regulatory circuitry (CRC) with Jun to overcome Yap dependency, which is distinct from the classic TGFb-induced EMT-TF network. A chemical-genetic screen and follow-up functional studies establish Brd4 as an epigenetic gatekeeper for the PTF-Jun CRC, and strong synergy between BET and Yap inhibitors in blocking PDAC growth.

ORGANISM(S): Mus musculus

PROVIDER: GSE224566 | GEO | 2023/03/02

REPOSITORIES: GEO

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Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [Cut&Tag]

Project description:Lineage plasticity has been proposed as a major source of intratumoral heterogeneity and therapeutic resistance. Employing an inducible genetic engineered mouse model, we illustrate that lineage plasticity enables advanced Pancreatic Ductal Adenocarcinoma (PDAC) tumors to develop spontaneous relapse following elimination of the central oncogenic driver - Yap. Transcriptomic and immunohistochemistry analysis of a large panel of PDAC tumors reveals that within high-grade tumors, small niches of PDAC cells gradually evolve to re-activate pluripotent transcription factors (PTFs), which lessen their dependency on Yap. Comprehensive Cut&Tag analysis demonstrate that although acquisition of PTF expression is coupled with the process of epithelial-to-mesenchymal transition (EMT), PTFs form a core transcriptional regulatory circuitry (CRC) with Jun to overcome Yap dependency, which is distinct from the classic TGFb-induced EMT-TF network. A chemical-genetic screen and follow-up functional studies establish Brd4 as an epigenetic gatekeeper for the PTF-Jun CRC, and strong synergy between BET and Yap inhibitors in blocking PDAC growth.

2023-01-11 | GSE210412 | GEO

Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2 [RNA-seq low input]

Project description:Pioneer transcription factors (PTF) can recognize their binding sites on nucleosomal DNA and trigger chromatin opening for recruitment of other non-pioneer transcription factors. However, critical properties of PTFs are still poorly understood, such as how can these transcription factors selectively recognize cell type-specific binding sites and under which conditions can they initiate chromatin remodelling. Here we show that early endoderm binding sites of the paradigm PTF Foxa2 are epigenetically primed by low levels of active chromatin modifications in embryonic stem cells (ESC). Priming of these binding sites is supported by preferential recruitment of Foxa2 to endoderm binding sites compared to lineage-inappropriate binding sites, when ectopically expressed in ESCs. We further show that binding of Foxa2 is required for chromatin opening during endoderm differentiation. However, increased chromatin accessibility was only detected on binding sites which are synergistically bound with other endoderm transcription factors. Thus, our data suggest that binding site selection of PTFs is directed by the chromatin environment and that chromatin opening requires collaboration of PTFs with additional transcription factors.

2019-07-26 | GSE116260 | GEO

Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2 [RNA-seq]

2019-07-26 | GSE116259 | GEO

Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2 [ChIP-seq Transcription Factors]

2019-07-26 | GSE116258 | GEO

Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2 [ChIP-seq Histone-Modifications]

2019-07-26 | GSE116257 | GEO

Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2 [ATAC-seq]

2019-07-26 | GSE116255 | GEO

Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2 [MeDIP-seq]

2019-07-26 | GSE116261 | GEO

Antithetical NFATc1-Sox2 and p53-miR-200 signalling networks governs pancreatic cancer cell plasticity and tumour progression

Project description:Pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial mesenchymal transdifferentiation (EMT) in adaption to environmental cues, including inflammation, a process that combines tumour cell dedifferentiation with dissemination and acquisition of stemness features. However, the mechanisms coupling inflammation-induced signalling pathways with EMT and stemness remain largely unknown. Here, we reveal the inflammation-induced transcription factor NFATc1 as a central regulator of pancreatic cancer cell plasticity.

2015-02-10 | E-MTAB-2324 | biostudies-arrayexpress

Dichotomous roles of Arid5a augment the immunosuppressive microenvironment of mesenchymal malignant tumors

Project description:Although mesenchymal subtypes of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are known as “immunologically cold” tumors, the molecular link between tumor immune evasiveness and mesenchymal phenotype remains largely unknown. Here, we show that AT-rich interaction domain-containing protein 5a (Arid5a), an RNA-binding protein, is involved in immune evasion in PDAC and CRC mouse models. Mass cytometry demonstrated that in tumors from Arid5a-deficient cells, the infiltration of granulocytic myeloid-derived suppressor cells and regulatory T cells is suppressed, but cytotoxic T-lymphocyte recruitment is enhanced. Mechanistically, Arid5a augmented Ido1 and Ccl2 expression by stabilizing these mRNAs in the PDAC model, but not Ido1 in the CRC model. Furthermore, Arid5a expression was substantially increased in mesenchymal subtypes of PDAC and CRC, mediated by ZEB1, and Arid5a promoted TGF-b-induced and IL6-induced epithelial-mesenchymal transition and acquisition of invasiveness in PDAC model cells. Thus, our findings demonstrate that Arid5a is a promising target for immunotolerant malignant tumors.

2021-04-07 | GSE159967 | GEO

Subtypes in human pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses

Project description:BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses. METHODS: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared. RESULTS: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were significantly more sensitive to simvastatin than poorly differentiated PDOs. CONCLUSIONS: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.

2021-08-07 | GSE181593 | GEO

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