HSP90 specific nIR probe identifies aggressive prostate cancers: a translational study from preclinical models to a human pilot study
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ABSTRACT:
PROVIDER: PRJNA692222 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13439022_1.fastq.gz | Fastqsanger.gz | |||
| SRR13439022_2.fastq.gz | Fastqsanger.gz | |||
| SRR13439023_1.fastq.gz | Fastqsanger.gz | |||
| SRR13439023_2.fastq.gz | Fastqsanger.gz | |||
| SRR13439024_1.fastq.gz | Fastqsanger.gz |
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Project description:Current screening modalities for prostate cancer rely on serologic testing for PSA and transrectal biopsy; however, many prostate cancers behave indolently.Because aggressively growing tumors depend on oncogenic drivers, we hypothesized that we could identify early, but aggressive prostate cancer,by an imaging modality targeting Hsp90, a chaperone for many molecules involved in oncogenic signaling. Previously we observedgreater avidity ofa probe,consisting of a near infrared dye tethered to an Hsp90 inhibitor,for cancers with greatermetastatic potential. We now report that an Hsp90 inhibitor-linked near infrared dye with greater tissue penetration could detect prostate cancers in preclinical models and in a phase I human clinical trial. These data, demonstrating specific uptake into aggressive tumors, in conjunction with our prior observations on photodynamic therapy guided by Hsp90 expression support a theranostic approach todetect and treatearly aggressive prostatecancers.
2022-01-01 | GSE164865 | GEO
Project description:A noninvasive test to discriminate indolent prostate cancers from lethal ones would focus treatment where necessary while reducing overtreatment. We exploited the known activity of heat shock protein 90 (Hsp90) as a chaperone critical for the function of numerous oncogenic drivers, including the androgen receptor and its variants, to detect aggressive prostate cancer. We linked a near-infrared fluorescing molecule to an HSP90 binding drug and demonstrated that this probe (designated HS196) was highly sensitive and specific for detecting implanted prostate cancer cell lines with greater uptake by more aggressive subtypes. In a phase I human study, systemically administered HS196 could be detected in malignant nodules within prostatectomy specimens. Single-cell RNA sequencing identified uptake of HS196 by malignant prostate epithelium from the peripheral zone (AMACR+ERG+EPCAM+ cells), including SYP+ neuroendocrine cells that are associated with therapeutic resistance and metastatic progression. A theranostic version of this molecule is under clinical testing.
| S-EPMC8742774 | biostudies-literature
Project description:To investigate the role of Nir in epidermis during embryogenesis, we crossed mice harboring conditional Nir alleles with the Krt14-Cre deleter strain, which results in Cre-mediated loss of Nir selectively in epidermis. Transciptome analysis of keratinocytes obtained from control and knock-out mice at E15.5 revealed 4393 genes differentially expressed between Nir knock-out and control mice (p-value<10-2). At E17.5, we found 5673 differentially expressed genes.
2018-03-05 | GSE102277 | GEO
Project description:Hsp90 is a molecular chaperone involved in the regulation and maturation of kinases and transcription factors. In Caenorhabditis elegans, it contributes to the development of fertility, maintenance of muscle structure, the regulation of heat-shock response and dauer state. To understand the consequences of Hsp90-depletion, we studied Hsp90 RNAi-treated nematodes by DNA microarrays and mass spectrometry. We find that upon development of phenotypes the levels of chaperones and Hsp90 cofactors are increased, while specific proteins related to the innate immune response are depleted. In microarrays, we further find many differentially expressed genes related to gonad and larval development. These genes form an expression cluster that is regulated independently from the immune response implying separate pathways of Hsp90-involvement. Using fluorescent reporter strains for the differentially expressed immune response genes skr-5, dod-24 and clec-60 we observe that their activity in intestinal tissues is influenced by Hsp90-depletion. Instead, effects on the development are evident in both gonad arms. After Hsp90-depletion, changes can be observed in early embryos and adults containing fluorescence-tagged versions of SEPA-1, CAV-1 or PUD-1, all of which are downregulated after Hsp90-depletion. Our observations identify molecular events for Hsp90-RNAi induced phenotypes during development and immune responses, which may help to separately investigate independent Hsp90-influenced processes that are relevant during the nematode’s life and development. We used microarrays to detail the global programme of gene expression after RNAi-mediated Hsp90 knock-down.
2017-10-17 | GSE105030 | GEO
Project description:microRNA-seq in circCDYL probe and NC probe
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Project description:We report the application of DNase-Seq (adapted from Hesselberth et al., 2009, as described in Zelin et al., 2012) to study the chromatin changes upon short Hsp90 depletion by exploiting temperature-sensitive allele G170D (Nathan and Lindquist, 1995). By generating ~43.6 million reads for wild type and 68.6 million reads for mutant, we were able to reconstitute the hypersensitivity maps under the regular conditions and under the conditions where Hsp90 was heat-inactivated. We find that there is a global reduction of open chromatin upon Hsp90 inactivation, as displayed by the decrease of total DHS size and the DHSs numbers. We also find that loss of Hsp90 leads to the increase of open chromatin at certain locations associated with chromatin remodelers such as RSC. Overall this study shows that short term improper functioning of Hsp90 results in genome-wide chromatin perturbations thereby demonstrating an Hsp90-dependence of chromatin architecture.
2016-11-03 | GSE88875 | GEO
Project description:Heat shock protein 90 (Hsp90) is essential for the stability and the function of many client proteins, such as ERB2, C-RAF, CDK4, HIF-1 aplha and AKT. Recent reports demonstrated that inhibition of Hsp90 modulates multiple functions required for survival of human cancer, such as myeloma (Mitsiades et al, Blood:107, 1092, 2006), The aim of this study is evaluate the effect of Hsp90 inhibition, and to identify molecular pathways responsible for anti-proliferative effect on ATL cells. For Hsp90 inhibition, Geldanamycin derivates, 17AAG (17-allylamino -17-demethoxygeldanamycin) and 17DMAG (17-(dimethylaminoethylamino) 17-demethoxygeldanamycin) were used in this study. Interleukin 2-independent ATL cell lines (MT-2 and MT-4) and an interleukin 2-dependent ATL cell line (TaY-E10) were incubated, with or without Hsp90 inhibitors.
2009-05-27 | GSE12287 | GEO
Project description:The heat shock protein 90 (Hsp90) chaperone functions as a protein-folding buffer and plays a unique role promoting the evolution of new heritable traits. To better understand how Hsp90 can affect mRNA translation we screened more than 1600 factors involved in mRNA regulation for physical interactions with Hsp90 in human cells. The mRNA binding protein CPEB2 strongly binds Hsp90 via its prion domain. In a yeast model, transient inhibition of Hsp90 resulted in persistent activation of a CPEB translation reporter even in the absence of exogenous CPEB that persisted for 30 generations after the inhibitor was removed. Ribosomal profiling revealed that some endogenous yeast mRNAs, including HAC1, show a persistent change in translation efficiency following transient Hsp90 inhibition. Thus, transient loss of Hsp90 function can promote a non-genetic inheritance of a translational state affecting specific mRNAs, introducing a new mechanism by which Hsp90 can promote phenotypic variation.
2020-08-11 | GSE153945 | GEO
Project description:The molecular chaperone HSP90 aids the maturation of a diverse but select set of metastable protein clients, many of which are key to a variety of signal transduction pathways. HSP90 function has been best investigated in animal and fungal systems, where inhibition of the chaperone has exceptionally diverse effects, ranging from reversing oncogenic transformation to facilitating the acquisition of drug resistance. Inhibition of HSP90 in the model plant Arabidopsis thaliana uncovers novel morphologies dependent on normally cryptic genetic variation and increases stochastic variation inherent to developmental processes. The biochemical activity of HSP90 is strictly conserved between animals and plants. However, the substrates and pathways dependent on HSP90 in plants are poorly understood. Progress has been impeded by reliance on light-sensitive HSP90 inhibitors due to redundancy in the A. thaliana HSP90 gene family. Here we present phenotypic and genome-wide expression analyses of A. thaliana with constitutively reduced HSP90 levels achieved by RNAi targeting. HSP90 reduction affects a variety of quantitative life-history traits, including flowering time and total seed set, and decreases developmental stability. Further, by quantitative analysis of morphological phenotypes, we demonstrate that HSP90-reduction increases phenotypic diversity in both seedlings and adult plants. Several morphologies are synergistically affected by HSP90 and growth temperature. Genome-wide expression analyses also suggest a central role for HSP90 in the genesis and maintenance of plastic responses. The expression results are substantiated by examination of the response of HSP90-reduced plants to attack by caterpillars of the generalist herbivore Trichoplusia ni. HSP90 reduction potentiates a more robust herbivore defense response. In sum, we propose that HSP90 exerts global effects on the environmental responsiveness of plants to many different stimuli. The comprehensive set of HSP90-reduced lines described here is a vital instrument to further examine the role of HSP90 as a central interface between organism, development, and environment. Experiment Overall Design: Three differerent experiments were performed. One experiment included lines RNAi-A1, RNAi-A3, and Control-2, with two biological replicates and one technical replicate per line. The second included lines RNAi-A2, RNAi-B1, RNAi-C1, Control-1, and Control-3, with three biological replicates per line. The third included the three single-isoform T-DNA insertion lines, along with the Col-0 control, with three biological replicates per line. See Sangster et al. "Phenotypic Diversity and Altered Environmental Plasticity in Arabidopsis thaliana with Reduced HSP90 Levels" for details of construct construction and further experimental rationale.
2008-06-15 | E-GEOD-7796 | biostudies-arrayexpress