Identification of early targets of SOX2 and PI3K signaling in normal, patient-derived tracheal basal cell lines.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE59866 | GEO | 2015/07/01
SECONDARY ACCESSION(S): PRJNA256931
REPOSITORIES: GEO
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Project description:Microarrays were used to examine gene expression changes in patient derived tracheal basal cell lines after treatment with Lenti-SOX2. Comparisons were made between baseline, Lenti-SOX2 and Lenti-SOX2 with a PI3K inhibitor (BKM120). Total RNA obtained from celll lnes 36 hours post lentivirus addition.
2015-07-01 | E-GEOD-59866 | biostudies-arrayexpress
Project description:Aberrant activation of PI3K pathway is frequently observed in triple negative breast cancer (TNBC). However single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor BKM120. Baseline and post-treatment PDX tumors harvested following 3 days of BKM120 or vehicle administration were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive PDX model at the completion of approximately 3-4 weeks of treatment. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increase in the levels of phosphorylated forms of Aurora kinases. Sensitivity to BKM120 was associated with higher baseline levels of proapoptotic markers (Bak and Caspase 3) and a greater number of markers differentially changed following BKM120 therapy. Interestingly, markers indicating PI3K pathway signaling activation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC.
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Project description:The goal is the characterization of the off-target activity of BKM120 observed in A2058 human melanoma cell line at IC90 concentration (3.606 µM) but not at lower concentrations. Controls are BEZ235, GDC0941, showing no off-target activity. A secondary objective is the characterizations of drug effects on transcript expression with respect to a control treatment (DMSO) of those PI3K inhibitors. 3 compounds, 3 concentrations per compound treatment, DMSO control treatement, 4 biological replicates
2012-06-30 | E-GEOD-33643 | biostudies-arrayexpress
Project description:The goal is the characterization of the off-target activity of BKM120 observed in A2058 human melanoma cell line at IC90 concentration (3.606 µM) but not at lower concentrations. Controls are BEZ235, GDC0941, showing no off-target activity. A secondary objective is the characterizations of drug effects on transcript expression with respect to a control treatment (DMSO) of those PI3K inhibitors.
2012-07-01 | GSE33643 | GEO
Project description:Sox2 has been studied in several types of human solid tumors. The investigators found that Sox2 had higher expression level in colorectal cancer and metastatic tissues than normal tissues. So the investigators assumed that whether Sox2 plays an important role in the progression and migration of colon cancer.
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Project description:SOX2 is a lineage specifier oncogene for lung squamous cell carcinoma (LSCC) and frequently amplified and overexpressed in human LSCC tumors (up to 90% of the cases). Our study demonstrated that SOX2 is a key determinant of neutrophil recruitment to tumors even in the absence of squamous histology. We generated cell lines from KrasLSL-G12D/+;Trp53fl/fl (KP) tumors that overexpress Sox2 (i.e. tumors from Lenti-Sox2-Cre infected KP mice that are validated to have Sox2 overexpression) (abbreviated as KPS) and employed chromatin immunoprecipitation sequencing (ChIP-seq) to identify genomic binding loci of SOX2 in KPS lines as well as Lkb1fl/fl;Ptenfl/fl (LP) LSCC tumors.
2018-10-16 | GSE118244 | GEO
Project description:Bronchopulmonary dysplasia remains one of the most common complication of prematurity, despite significant improvements in perinatal care. Functional modeling of human lung development and disease, like BPD, is limited by our ability to access the lung and to maintain relevant stem cell populations in culture. Single cell RNA-sequencing confirmed the presence of epithelial cells in tracheal aspirates obtained from intubated neonates. Using combined SMAD signaling inhibition and mTOR inhibition neonatal tracheal-aspirate derived (nTAD) basal stem cells can be expanded long-term and retain the ability to differentiate into pseudo-stratified airway epithelium. Conclusions: Our data demonstrate that neonatal tracheal aspirate-derived epithelial cells can provide a novel ex vivo human cellular model to study neonatal lung development and disease.
2020-09-21 | GSE137950 | GEO
Project description:Bronchopulmonary dysplasia remains one of the most common complication of prematurity, despite significant improvements in perinatal care. Functional modeling of human lung development and disease, like BPD, is limited by our ability to access the lung and to maintain relevant stem cell populations in culture. Single cell RNA-sequencing confirmed the presence of epithelial cells in tracheal aspirates obtained from intubated neonates. Using combined SMAD signaling inhibition and mTOR inhibition neonatal tracheal-aspirate derived (nTAD) basal stem cells can be expanded long-term and retain the ability to differentiate into pseudo-stratified airway epithelium. Conclusions: Our data demonstrate that neonatal tracheal aspirate-derived epithelial cells can provide a novel ex vivo human cellular model to study neonatal lung development and disease.
2020-04-15 | GSE137353 | GEO
Project description:Aberrant activation of PI3K pathway is frequently observed in triple negative breast cancer (TNBC). However single agent PI3K inhibitors have shown modest anti-tumor activity. To investigate biomarkers of response, we tested 17 TNBC PDX models with diverse genetic and proteomic background, with varying PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor BKM120 as well as baseline and treatment induced proteomic changes as assessed by reverse phase protein array (RPPA). We demonstrated that PI3K inhibition induces varying degrees of tumor growth inhibition (TGI), with 5 models demonstrating over 80% TGI. BKM120 consistently reduced PI3K pathway activity as demonstrated by reduced pAKT following therapy. Several biomarkers showed significant association with resistance, including baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment induced increase in the levels of phosphorylated forms of Aurora kinases. Sensitivity was associated with higher baseline levels of proapoptotic markers (Bak and Caspase 3) and higher number of markers being changed following BKM120 therapy. Interestingly, markers indicating PI3K pathway signaling activation at baseline were not significantly correlated to %TGI. These results provide important insights in biomarker development for PI3K inhibitors in TNBC.
2020-12-31 | GSE148949 | GEO