Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1237234 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: The goal of this study is to establish and molecularly characterize non-small cell lung cancer (NSCLC) organoids. Generation of NSCLC organoids would provide additional preclinical models for drug screening and biomarker discovery. Methods: Patient lung tumors and previously established patient-derived xenografts (PDX) were processed to generate organoids. Total RNA was extracted and subjected to RNA-seq to examine the gene expression similarity between patient/PDX/organoid of the same model using t-SNE clustering. Results: Through RNA-sequencing, we generated TPM values of patient, PDX and organoid samples of 5 models. t-SNE analysis showed that the patient/PDX/organoid of the same models clustered together. The lung adenocarcinoma samples formed a separate cluster from the squamous cell carcinoma samples based on gene expression. Conclusions: Our study introduces the establishment of NSCLC organoids and demonstrates the gene expession similarity of the organoid model to its corresponding PDX and patient sample.
2019-11-26 | GSE119004 | GEO
Project description:Patient-derived parathyroid organoids as tracer and drug-screening application model
| PRJNA810360 | ENA
Project description:Using patient derived lung cancer organoids to predict clinical response and find theraputic mechanisms
2022-09-26 | PXD037076 |
Project description:Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells and lung organoids. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression in both human cardiac and lung epithelial cells and protected hESC-derived lung organoids against SARS-CoV-2 infection. To build an in vitro model of viral infection in human lung tissue, we set out to generate lung organoids from hESC using a slightly modified combination of previously established differentiation methods (Carvalho et al., 2019; Jacob et al., 2017; Miller et al., 2019). We performed single cell RNA sequencing of fully differentiated organoids to unbiasedly characterize the cell types present and validate them as a model of SARS-CoV-2 infection and antiandrogenic drug treatment.
2020-12-15 | GSE161263 | GEO
Project description:Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells and lung organoids. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression in both human cardiac and lung epithelial cells and protected hESC-derived lung organoids against SARS-CoV-2 infection. To build an in vitro model of viral infection in human lung tissue, we set out to generate lung organoids from hESC using a slightly modified combination of previously established differentiation methods (Carvalho et al., 2019; Jacob et al., 2017; Miller et al., 2019). We performed single cell RNA sequencing of fully differentiated organoids to unbiasedly characterize the cell types present and validate them as a model of SARS-CoV-2 infection and antiandrogenic drug treatment.
2020-12-15 | GSE161262 | GEO
Project description:The RNF43_G659fs mutation occurs frequently in colorectal cancer, however, its function remains poorly understood. In addition, there are no specific therapies directed against this alteration. In this study, we found that RNF43_G659fs is not a passenger mutation, but rather promotes cell growth independent of Wnt signaling. We performed a drug repurposing library screen and discovered that cells with RNF43_G659 mutations were selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yielded promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_G659fs mutations. We found that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination. Additionally, RNA-sequencing of RNF43659mut isogenic cells revealed decreased interferon signaling that may alter tumor immunity. Our findings suggest a novel therapeutic application for PI3K/mTOR inhibitors in treating RNF43_G659fs mutant cancers.
2022-03-27 | GSE179464 | GEO
Project description:Stem-cell-derived epithelial organoids are routinely used for the biological and biomedical modelling of tissues. However, the complexity, lack of standardization and quality control of stem cell culture in solid extracellular matrices hampers the routine use of the organoids at industrial scale. Here, we report the fabrication of microengineered cell-culture devices and scalable and automated methods for the suspension culture and real-time analysis of thousands of individual gastrointestinal organoids trapped in microcavity arrays within a polymer-hydrogel substrate. The absence of a solid matrix significantly reduces organoid heterogeneity, as we show for mouse and human gastrointestinal organoids. We used the devices to screen for anticancer drug candidates with patient-derived colorectal cancer organoids, and high-content image-based phenotypic analyses to reveal insights into drug-action mechanisms. The scalable organoid-culture technology should facilitate the use of organoids in drug development and diagnostics.
2020-04-10 | GSE148347 | GEO
Project description:Modeling Lung Adenocarcinoma Metastases Using Patient-Derived Organoids
| PRJNA1157185 | ENA
Project description:Preclinical models of breast cancer that better predict patient-specific drug responses are critical for expanding the clinical utility of targeted therapies, including for inhibitors of poly(ADP-ribose) polymerase (PARP). Reprogramming primary cancer cells into human induced pluripotent stem cells (hiPSCs) recently emerged as a powerful tool to model drug response phenotypes, but its use to date has been limited to hematopoietic malignancies. We designed an optimized reprogramming methodology to generate breast cancer-derived hiPSCs (BC-hiPSCs) from nine patients representing all major subtypes of breast cancer. BC-hiPSCs retain patient-specific oncogenic variants, including variants unique to individual tumor subclones. Additionally, we developed a protocol to differentiate BC-hiPSCs into mammary epithelial cells and mammary-like organoids for in vitro disease modeling, including drug response phenotyping. Using these tools, we demonstrated that BC-hiPSCs can be used to screen for differential sensitivity to PARP inhibitors and mechanistically investigated the causal genetic variant driving drug sensitivity in one patient.
2025-02-19 | GSE272395 | GEO
Project description:Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated metabolism might lead to excessive inflammatory and autoimmune responses as observed in severe and long COVID-19 patients. Here we show that SARS-CoV-2 modulates cellular metabolism and reduces autophagy. Accordingly, compound-driven induction of autophagy limits SARS-CoV-2 propagation. In detail, SARS-CoV-2-infected cells show accumulation of key metabolites, activation of autophagy inhibitors (AKT1, SKP2) and reduction of proteins responsible for autophagy initiation (AMPK, TSC2, ULK1), membrane nucleation, and phagophore formation (BECN1, VPS34, ATG14), as well as autophagosome-lysosome fusion (BECN1, ATG14 oligomers). Consequently, phagophore-incorporated autophagy markers LC3B-II and P62 accumulate, which we confirm in a hamster model and lung samples of COVID-19 patients. Single-nucleus and single-cell sequencing of patient-derived lung and mucosal samples show differential transcriptional regulation of autophagy and immune genes depending on cell type, disease duration, and SARS-CoV-2 replication levels. Targeting of autophagic pathways by exogenous administration of the polyamines spermidine and spermine, the selective AKT1 inhibitor MK-2206, and the BECN1-stabilizing anthelmintic drug niclosamide inhibit SARS-CoV-2 propagation in vitro with IC<sub>50</sub> values of 136.7, 7.67, 0.11, and 0.13 μM, respectively. Autophagy-inducing compounds reduce SARS-CoV-2 propagation in primary human lung cells and intestinal organoids emphasizing their potential as treatment options against COVID-19.
2021-06-11 | MTBLS2840 | MetaboLights