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E-MTAB-10041

ABSTRACT: RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

PROVIDER: E-MTAB-10041 | ExpressionAtlas | 2024-11-14

REPOSITORIES: ExpressionAtlas

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			Action	DRS
	E-MTAB-10041-analysis-methods.tsv	Tabular
	E-MTAB-10041-analytics.tsv	Tabular
	E-MTAB-10041-atlasExperimentSummary.Rdata	Rdata
	E-MTAB-10041-configuration.xml	Xml
	E-MTAB-10041-g3_g1-mvaPlot.png	Other

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Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

Project description:Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

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RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

Project description:RNA-seq of mouse colon to investigate how suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity

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Induction of ER stress in HCT116 colon cancer cells

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Heat Shock Factor 1-dependent extraceHeat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancerllular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer

Project description:Chronic inflammation underlies tumor initiation, progression, invasion, and metastasis. In the colon, long-term exposure to chronic inflammation drives colitis associated colon cancer (CAC) in patients with inflammatory bowel disease (IBD). While the causal and clinical links between chronic inflammation and CAC are well established, our molecular understanding of how chronic inflammation leads to the development of colon cancer is still lacking. Here we deconstruct the evolving microenvironment of CAC, by measuring proteomic changes and extracellular matrix (ECM) organization over time in a genetically modified mouse model of CAC. We detect early changes in ECM structure and composition, and report that the transcriptional regulator heat shock factor 1 (HSF1) plays a crucial role in orchestrating these events. Activated in stromal fibroblasts of the gut, HSF1 promotes ECM remodeling and inflammatory programs which lead to the development of CAC. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell culture, prevents inflammation-induced ECM remodeling in mice and significantly inhibits progression to CAC. Establishing the relevance of our experimental findings to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer.

2020-11-05 | PXD022207 | Pride

Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition

Project description:The heat-shock protein 90 (HSP90) is a promising target in cancer therapy, but its inhibitors' clinical trial failures are partly due to a compensatory heat-shock response (HSR) mediated by heat-shock factor 1 (HSF1). We previously showed that wildtype p53 reduces HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here, we explore if simultaneous p53 activation or cell cycle inhibition can disrupt the HSF1-HSR axis and enhance HSP90 inhibitors' efficiency. mRNA sequencing was performed on HCT116 cells treated for 24 hours with DMSO, 50 nM Ganetespib, 1 µM RG-7388, or their combination. We found that the p53 activator Idasanutlin suppresses HSF1-HSR activity in HSP90 inhibitor-based therapies, synergistically reducing cell viability and accelerating cell death in p53-proficient colorectal cancer (CRC) cells and organoids. Combination therapy upregulates p53 pathways, apoptosis, and inflammation. In a CRC mouse model, dual HSF1-HSP90 inhibition represses tumor growth and alters immune cell composition. CDK4/6 inhibition under HSP90 inhibition mimics HSR repression in p53-proficient CRC cells. In p53-deficient CRC cells and p53-mutated organoids, combined HSP90 and CDK4/6 inhibition suppresses HSF1-HSR and reduces cancer growth, offering a p53-independent strategy for CRC treatment. In conclusion, we present new options to improve HSP90-based therapies for enhanced CRC treatment.

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Induction of ER stress in HCT116 colon cancer cells

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Project description:Hyper-activation of the PI 3-Kinase/ AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, upon partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the co-deletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN-mutant prostate cancer to life-threatening disease. To better assess the role of Phlpp in prostate we performed micorarray analysis of gene expression in the WT and Pten+/-; Phlpp1-/- mice.

2011-08-16 | E-GEOD-30987 | biostudies-arrayexpress

E-MTAB-10036

Project description:RNA-seq of mouse colon to investigate how influenza infection leads to intestinal disorders

2021-03-22 | E-MTAB-10036 | ExpressionAtlas