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Dormancy-inducing 3D engineered matrix uncovers mechanosensitive and drug-protective FHL2-p21 signaling axis

ABSTRACT: Dormancy-inducing 3D engineered matrix uncovers mechanosensitive and drug-protective FHL2-p21 signaling axis

PROVIDER: PRJNA757002 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15567326_1.fastq.gz	Fastqsanger.gz
	SRR15567326_2.fastq.gz	Fastqsanger.gz
	SRR15567327_1.fastq.gz	Fastqsanger.gz
	SRR15567327_2.fastq.gz	Fastqsanger.gz
	SRR15567328_1.fastq.gz	Fastqsanger.gz

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Dormancy-inducing 3D engineered matrix uncovers mechanosensitive and drug-protective FHL2-p21 signaling axis

Project description:Solid cancers frequently relapse with distant metastasis, despite local and systemic treatment. Cellular dormancy has been identified as an important mechanism underlying drug resistance enabling late relapse. Therefore, relapse from invisible, minimal residual cancer of seemingly disease-free patients call for in vitro models of dormant cells suited for drug discovery. Here, we explore dormancy-inducing 3D engineered matrices, which generate mechanical confinement and induce growth arrest and survival against chemotherapy in cancer cells. We characterized the dormant phenotype of solitary cells by P-ERKlow:P-p38high dormancy signaling ratio, along with Ki67− expression. As underlying mechanism, we identified stiffness-dependent nuclear localization of the four-and-a-half LIM domain 2 (FHL2) protein, leading to p53-independent high p21Cip1/Waf1 nuclear expression, validated in murine and human tissue. Suggestive of a resistance-causing role, cells in the dormancy-inducing matrix became sensitive against chemotherapy upon FHL2 down-regulation. Thus, our biomaterial-based approach will enable systematic screens for previously unidentified compounds suited to eradicate potentially relapsing dormant cancer cells.

2024-08-21 | GSE182606 | GEO

Autophagy inhibition elicits emergence from metastatic dormancy by inducing and stabilizing Pfkfb3

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Effect of CDK8/19 inhibitor Senexin A on p21-regulated gene expression in human HT1080 p21-9 cells with IPTG-inducible p21

Project description:p21 (CDKN1A) expression from an IPTG-inducible promoter in HT1080 p21-9 cells was previously shown to inhibit a set of genes, many of which are involved in cell cycle progression, and to upregulate another set of genes, some of which have been implicated in cancer and age-related diseases. We have now developed Senexin A, a small-molecule inhibitor of p21-induced transcription, which we found to be a selective inhibitor of CDK8 and CDK19. Here we tested the effect of Senexin A on the induction and inhibition of transcription by p21. In this dataset, we include microarray gene expression data from samples of HT1080 p21-9 cells that were either untreated, treated with p21-inducing IPTG alone, with Senexin A alone, or with IPTG and Senexin A. This experiment shows that Senexin A inhibits primarily the induction but not the inhibition of gene expression by p21. The data for each of the four samples were normalized to the sample from untreated cells, using GeneSpring GX. Fold changes in gene expression upon the addition of IPTG with or without Senexin A were compared using Microsft Excel. Changes in the expression of specific GO categories of genes were compared using GeneSpring.

2012-08-12 | E-GEOD-39464 | biostudies-arrayexpress

Effect of CDK8/19 inhibitor Senexin A on p21-regulated gene expression in human HT1080 p21-9 cells with IPTG-inducible p21

2012-08-13 | GSE39464 | GEO

Protein aggregation is a consequence of the dormancy-inducing membrane toxin TisB in Escherichia coli

Project description:Protein aggregates occur in all living cells due to misfolding of proteins. In bacteria, protein aggregation is associated with cellular inactivity, which is related to dormancy and tolerance to stressful conditions, including the exposure to antibiotics. In Escherichia coli, the membrane toxin TisB is an important factor for dormancy and antibiotic tolerance upon DNA damage mediated by the fluoroquinolone antibiotic ciprofloxacin. Here, we show that TisB provokes protein aggregation in response to ciprofloxacin. The stress response and TisB-dependent protein aggregates are analyzed by LC-MS.

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Analysis of the stress response after induction of the dormancy-inducing membrane toxin TisB in Escherichia coli

Project description:Analysis of the stress response after induction of the dormancy-inducing membrane toxin TisB in Escherichia coli

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Cellular adhesion promotes prostate cancer cells escape from dormancy

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2015-10-26 | E-GEOD-64262 | biostudies-arrayexpress

Colonization of distant organs by mechanosensitive tumor cells via generation of stable circulating homotypic clusters

Project description:Mechanisms governing cancer metastasis remain poorly understood. Once disseminated tumor cells (DTCs) arrive at a metastatic organ, they remain there, latent, and become seeds of metastasis. However, the clonal composition of DTCs in a latent state remains unclear. Here, we applied high-resolution DNA barcode tracking to a mouse model that recapitulated the metastatic dormancy of head and neck squamous cell carcinoma (HNSCC). We found that clones that had abundant circulating tumor cells (CTCs) but were rare in the primary site dominated DTCs. We obtained a specific subclone that dominated CTCs and subsequent DTCs in lungs and bone marrow. Despite no notable features under static conditions, this clone significantly generated stable cell aggregates that were resistant to anoikis in suspension culture under fluid shear stress conditions. Even as a heterogeneous population, this clone generated almost monoclonal CTC clusters. Via transcriptome analyses, we identified E-cadherin to be indispensable but not sufficient for such stable cell-cell adhesion. Instead, our data indicated that mutual regulation of cortical actin-myosin dynamics according to mechanostress in the cells within each aggregate governed stable adhesion. Furthermore, the gene expression signature of the mechanosensitive clone, which originated clustered CTCs, was associated with locoregional and metastatic recurrence in patients with HNSCC. These results reveal that intrinsically mechanosensitive rare clones in the parental population dominantly colonize distant sites via homotypic CTC cluster formation. This novel clonal selection mechanism based on intrinsic tumor cell mechanosensitivity may lead to promising cancer therapies.

2020-10-03 | GSE158933 | GEO

Pasteuria ramosa strain:P21 | isolate:P21

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