Differentially expressed genes between the bone metastatic subpopulations and lung metastatic subpopulations of lung adenocarcinoma
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ABSTRACT:
PROVIDER: PRJNA1048876 | ENA |
REPOSITORIES: ENA
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Project description:To define the molecular underpinning of LUAD bone metastasis, we performed high-throughput transcriptome sequencing (RNA-seq) using total RNA from LuM and BoM cell subpopulations. Afterwards, differentially expressed genes were used for further analysis.
2024-06-30 | GSE249364 | GEO
Project description:Differentially expressed SE-lncRNAs in lung adenocarcinoma
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Project description:Lung cancer is the leading cause of cancer death both in men and women. Tumor heterogeneity is an impediment to targeted treatment of all cancers, including lung cancer. Here, we sought to characterize changes in tumor proteome and phosphoproteome by longitudinal, prospective collection of tumor tissue of an exceptional responder lung adenocarcinoma patient who survived with metastatic lung adenocarcinoma for more than seven years with HER2-directed therapy in combination with chemotherapy. We employed “Super-SILAC” and TMT labeling strategies to quantify the proteome and phosphoproteome of a lung metastatic site and ten different metastatic progressive lymph nodes collected across a span of seven years, including five lymph nodes procured at autopsy. We identified specific signaling networks enriched in lung compared to the lymph node metastatic sites. We correlated the changes in protein abundance with changes in copy number alteration (CNA) and transcript expression. To further interrogate the mass spectrometry data, patient-specific database was built incorporating all the somatic variants identified by whole genome sequencing (WGS) of genomic DNA from the lung, one lymph node metastatic site and blood. An extensive validation pipeline was built for confirmation of variant peptides. We validated 360 spectra corresponding to 55 germline and 6 somatic variant peptides. Targeted MRM assays demonstrated expression of two novel variant somatic peptides, CDK12 G879V and FASN-R1439Q, with expression in lung and lymph node metastatic sites, respectively. CDK12 G879V mutation likely results in a nonfunctional kinase and knockdown of CDK12 in lung adenocarcinoma cells increased chemotherapy sensitivity, explaining the complete resolution of the lung metastatic sites in this patient.
2019-01-07 | PXD010779 | Pride
Project description:The purpose of this study was to identify gene targets differentially regulated by shRNA-mediated knockdown of the HSF1 transcription factor in the brain-metastatic lung adenocarcinoma cell line PC9-BrM3.
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Project description:Exploring differentially expressed miRNAs (DEmiRNAs) in plasma sample between lung adenocarcinoma patients and healthy people using a small RNA (sRNA) sequencing,results showed that we could used these DEmiRNAs identified could discriminate healthy peoples from lung adenocarcinoma patients. In present study, we applied an RNA sequencing (RNA-seq) approach to explore the differentially expressed miRNAs (DEmiRNAs) in plasma sample between 6 lung adenocarcinoma patients and 4 healthy people.
2021-03-09 | GSE151963 | GEO
Project description:Inactivation of the retinoblastoma (RB) tumor suppressor in lung adenocarcinoma is associated with the rapid acquisition of metastatic ability and the loss of lung cell lineage commitment. We previously showed that restoration of RB in advanced lung adenocarcinomas in the mouse was correlated with a decreased frequency of lineage de-committed tumors and overt metastases. To identify a causal relationship for RB and its role in reprogramming lineage commitment and reducing metastatic competency in lung adenocarcinoma, we developed multiple tumor spheroid forming lines where RB restoration could be achieved after characterization of the degree of each spheroid’s lineage commitment and metastatic ability. Surprisingly, we discovered that RB inactivation dramatically promoted tumor spheroid forming potential in tumors that arise in the KrasLSL-G12D/+; p53flox/flox lung adenocarcinoma model. However, RB reactivation had no effect on the maintenance of tumor spheroid lines once established. Additionally, we show that RB-deficient tumor spheroid lines are not uniformly metastatically competent but are equally likely to be non-metastatic. Interestingly, unlike tumor spheroid maintenance, RB restoration could functionally revert metastatic tumor spheroids to a non-metastatic cell state. Thus, strategies to reinstate RB-pathway activity in lung cancer may reverse metastatic ability and have therapeutic potential. Finally, the acquisition of tumor spheroid forming potential reflects underlying cell state plasticity, which is often predictive of, or even conflated with metastatic ability. Our data support that each is a discrete cell state restricted by RB and question the suitability of tumor spheroid models for their predictive potential of advanced metastatic tumor cell states.
2023-08-14 | GSE240511 | GEO
Project description:Characterizing an HSF1-dependent transcriptional program in metastatic lung adenocarcinoma
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Project description:Background: Lung adenocarcinoma (LUAD) is the leading cause of deaths worldwide, and metastasis accounts for the vast majority of cancer-related deaths. Driver mutations play important roles in treatment decision making for LUAD patients, while the complicated metastatic progress cannot be explained by genetic aberrations alone. Epigenomic reprogramming is particularly notable as an important signature of the metastasis transition. However, long noncoding RNAs (lncRNAs) hijacked by super-enhancer (SE), vital regulatory elements in epigenome, remain elusive in the progression of metastasis. Methods: SE associated lncRNAs microarray was utilized to identified the dysregulated lncRNAs related to metastasis. ChIP-seq, Hi-C data analysis and luciferase reporter assay were utilized to confirm LINC01977 was hijacked by SE. In vitro and in vivo assays were applied to elucidate effects of LINC01977 on the malignancy of LUAD. Results: In this study, we identified that LINC01977, a cancer-testis lncRNA, was up-regulated in tumor, which was driven by a …kb-long SE upstream of LINC01977 and sensitive to BRD4 inhibitor. LINC01977-antisense oligonucleotides (ASO) dramatically suppresses proliferation and invasion both in vitro and in vivo. Mechanically, LINC01977 promotes phosphorylation of SMAD3 to facilitate its nuclear retention, and it also act as a scaffold to cooperate the interaction between SMAD3 and CBP/P300, the transcriptional co-activators, to regulate the downstream target gene ZEB1. Interestingly, SMAD3 also positively regulated LINC09177 transcription by binding the promoter and active elements of its SE, which was medicated by canonical TGF-β signaling secreted by M2-like tumor-associated macrophages (TAM2). We also revealed that the expression of LINC01977 was positively correlated with TAM2 infiltration especially in early stage. Additionally, stage I LUAD patients with high LIN01977 expression predicated a shorter progression-free survival (PFS). Conclusions: LINC01977 promotes the malignant progression of LUAD through facilitating the interaction between SMAD3 and CBP/P300. The upregulation of LINC01977 was medicated by super-enhancer and TAM2 infiltration, dependent on canonical TGF-β signaling. LINC01977 could be a valuable therapeutic target especially for early stage patients.
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Project description:The model is based on publication:
Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification
Abstract:
Gefitinib, one of the tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR), is effective for treating lung adenocarcinoma harboring EGFR mutation; but later, most cases acquire a resistance to gefitinib. One of the mechanisms conferring gefitinib resistance to lung adenocarcinoma is the amplification of the MET gene, which is observed in 5–22% of gefitinib-resistant tumors. A previous study suggested that MET amplification could cause gefitinib resistance by driving ErbB3-dependent activation of the PI3K pathway. In this study, we built a mathematical model of gefitinib resistance caused by MET amplification using lung adenocarcinoma HCC827-GR (gefitinib resistant) cells. The molecular reactions involved in gefitinib resistance consisted of dimerization and phosphorylation of three molecules, EGFR, ErbB3, and MET were described by a series of ordinary differential equations. To perform a computer simulation, we quantified each molecule on the cell surface using flow cytometry and estimated unknown parameters by dimensional analysis. Our simulation showed that the number of active ErbB3 molecules is around a hundred-fold smaller than that of active MET molecules. Limited contribution of ErbB3 in gefitinib resistance by MET amplification is also demonstrated using HCC827-GR cells in culture experiments. Our mathematical model provides a quantitative understanding of the molecular reactions underlying drug resistance.
2024-09-02 | BIOMD0000000827 | BioModels