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Enhancer remodeling promotes resistance to epigenetic-targeted therapy and engenders tumor cell vulnerabilities

ABSTRACT: Enhancer remodeling promotes resistance to epigenetic-targeted therapy and engenders tumor cell vulnerabilities

PROVIDER: PRJNA421166 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6348260.fastq.gz	Fastqsanger.gz
	SRR6348261.fastq.gz	Fastqsanger.gz
	SRR6348262.fastq.gz	Fastqsanger.gz
	SRR6348263.fastq.gz	Fastqsanger.gz
	SRR6348264.fastq.gz	Fastqsanger.gz

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Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling.

Project description:Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically targeted drugs remain largely unexplored. We used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the phosphatidylinositol 3-kinase (PI3K) pathway as promoting resistance to BET inhibition. Transcriptomic and chromatin profiling of resistant cells revealed that global enhancer remodeling is associated with upregulation of receptor tyrosine kinases (RTKs), activation of PI3K signaling, and vulnerability to RTK/PI3K inhibition. Large-scale combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations. These studies provide a roadmap to elucidate resistance to epigenetic-targeted therapeutics and inform efficacious combination therapies.

| S-EPMC6352909 | biostudies-literature

Enhancer remodeling promotes resistance to epigenetic-targeted therapy and engenders tumor cell vulnerabilities

Project description:Drug resistance is a major clinical challenge in achieving durable responses to targeted cancer therapeutics. Resistance mechanisms to new classes of epigenetic-targeted drugs entering the clinic remain largely unexplored. We used BET inhibition in MYCN-amplified neuroblastoma as a prototype to model innate and acquired resistance to chromatin remodeling inhibitors in cancer. Genome-scale, pooled lentiviral ORF and CRISPR knockout rescue screens nominated the PI3K pathway as a key signaling node that mediates resistance to BET inhibition.

2018-12-13 | GSE107706 | GEO

Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer

Project description:Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer

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BRD4 connects enhancer remodeling to senescence immune surveillance

Project description:BRD4 connects enhancer remodeling to senescence immune surveillance

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Global profiling of cancer cell recovery from therapy-induced stress reveals druggable vulnerabilities

Project description:Cancer cells survive therapy-induced stress, but how they resolve it is not clear. Using an integrated systems level approach we delineate the global mechanisms of cellular recovery from proteotoxic stress. Our findings in proteasome inhibitor-treated myeloma cells provide a layered chart of the protracted processes of stress resolution that encompass extensive metabolic changes. Tumour cells that have survived proteasome inhibition and are recovering from proteotoxic injuries are more vulnerable to certain insults than acutely stressed or unstressed cells. We identify mitochondria and the GCN2-driven cellular response to amino acid depletion as examples of recovery-associated vulnerabilities, and demonstrate that GCN2 is a bona fide target in transcriptional signature-defined subsets of solid cancers irrespective of prior proteasome inhibition. Thus, targeting multi-system vulnerabilities tied to cellular recovery from drug-induced stress has the potential to optimise cancer therapies.

2021-04-15 | GSE158387 | GEO

Determination of the tumor microenvironment remodeling by KRAS targeted therapy in pancreatic cancer

Project description:Determination of the tumor microenvironment remodeling by KRAS targeted therapy in pancreatic cancer

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Global profiling of cancer cell recovery from therapy-induced stress reveals druggable vulnerabilities

Project description:Global profiling of cancer cell recovery from therapy-induced stress reveals druggable vulnerabilities

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Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription

Project description:Recent studies suggest a hierarchical model in which lineage-determining factors act in a collaborative manner to select and prime cell-specific enhancers, thereby enabling signal-dependent transcription factors to bind and function in a cell type-specific manner. Consistent with this model, TLR4 signaling primarily regulates macrophage gene expression through a pre-existing enhancer landscape. However, TLR4 signaling also induces priming of ~3000 enhancer-like regions de novo, enabling visualization of intermediates in enhancer selection and activation. Unexpectedly, we find that enhancer transcription precedes local mono- and di-methylation of histone H3 lysine 4 (H3K4me1/2). H3K4 methylation at de novo enhancers is primarily dependent on the histone methyltransferases Mll1, Mll2/4 and Mll3, and is significantly reduced by inhibition of RNA polymerase II elongation. Collectively, these findings suggest an essential role of enhancer transcription in H3K4me1/2 deposition at de novo enhancers that is independent of potential functions of the resulting eRNA transcripts. ChIP-Seq and Gro-Seq profiling was performed in thioglycollate-elicited peritoneal macrophages, PU.1-/- and PUER cells treated as indicated.

2013-08-09 | E-GEOD-48759 | biostudies-arrayexpress

Graham2013 - Role of osteocytes in targeted bone remodeling

Project description:Jason M. Graham, Bruce P. Ayati, Sarah A. Holstein & James A. Martin. The role of osteocytes in targeted bone remodeling: a mathematical model. PLoS ONE 8, 5 (2013). Until recently many studies of bone remodeling at the cellular level have focused on the behavior of mature osteoblasts and osteoclasts, and their respective precursor cells, with the role of osteocytes and bone lining cells left largely unexplored. This is particularly true with respect to the mathematical modeling of bone remodeling. However, there is increasing evidence that osteocytes play important roles in the cycle of targeted bone remodeling, in serving as a significant source of RANKL to support osteoclastogenesis, and in secreting the bone formation inhibitor sclerostin. Moreover, there is also increasing interest in sclerostin, an osteocyte-secreted bone formation inhibitor, and its role in regulating local response to changes in the bone microenvironment. Here we develop a cell population model of bone remodeling that includes the role of osteocytes, sclerostin, and allows for the possibility of RANKL expression by osteocyte cell populations. We have aimed to give a simple, yet still tractable, model that remains faithful to the underlying system based on the known literature. This model extends and complements many of the existing mathematical models for bone remodeling, but can be used to explore aspects of the process of bone remodeling that were previously beyond the scope of prior modeling work. Through numerical simulations we demonstrate that our model can be used to explore theoretically many of the qualitative features of the role of osteocytes in bone biology as presented in recent literature.

2024-09-02 | BIOMD0000000721 | BioModels

SETD2 Loss Creates A Permissive Epigenetic Landscape that Promotes Kidney Cancer Metastasis and Engenders Therapeutic Vulnerabilities

Project description:SETD2 Loss Creates A Permissive Epigenetic Landscape that Promotes Kidney Cancer Metastasis and Engenders Therapeutic Vulnerabilities

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