Evaluating the effects of PTEN loss-driven cell transformation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE229554 | GEO | 2024/04/01
REPOSITORIES: GEO
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Project description:A wealth of proteogenomic data has been generated using cancer samples to deepen our understanding of the mechanisms of cancer and how biological networks are altered in association with somatic mutation of tumor suppressor genes, such as TP53 and PTEN. To generate functional signatures of TP53 or PTEN loss, we profiled the RNA and phosphoproteomes of the MCF10A epithelial cell line, along with its congenic TP53- or PTEN-knockout derivatives, upon perturbation with the monofunctional DNA alkylating agent methyl methanesulfonate (MMS) vs. mock-treatment. To enable quantitative and reproducible mass spectrometry data generation, the cell lines were SILAC-labeled (stable isotope labeling with amino acids in cell culture), and the experimental design included label swapping and biological replicates. All data are publicly available and may be used to advance our understanding of the TP53 and PTEN tumor suppressor genes and to provide functional signatures for bioinformatic analyses of proteogenomic datasets.
2023-11-20 | PXD028494 | Pride
Project description:In an effort to identify genes whose expression is regulated by activated PI3K signaling, we performed microarray analysis and subsequent qRT-PCR on an isogenic set of PTEN gene-targeted human cancer cells. Numerous p53 effectors were upregulated following PTEN deletion, including p21, GDF15, PIG3, NOXA, and PLK2. Stable depletion of p53 led to reversion of the gene expression program. Western blots revealed that p53 was stabilized in HCT116 PTEN-/- cells via an Akt1-dependent and p14ARF-independent mechanism. Stable depletion of PTEN in untransformed human fibroblasts and epithelial cells also led to upregulation of p53 and senescent-like growth arrest. Simultaneous depletion of p53 rescued this phenotype, enabling PTEN-depleted cells to continue proliferating. Next, we tested whether oncogenic PIK3CA, like inactivated PTEN, could activate p53. Retroviral expression of oncogenic human PIK3CA in MCF10A cells led to activation of p53 and upregulation of p53-regulated genes. Stable depletion of p53 reversed these PIK3CA-induced expression changes and synergized with oncogenic PIK3CA in inducing anchorage-independent growth. Finally, targeted deletion of an endogenous allele of oncogenic but not wild-type PIK3CA in a human cancer cell line led to a reduction in p53 levels and a decrease in the expression of p53-regulated genes. These studies demonstrate that activation of PI3K signaling by mutations in PTEN or PIK3CA can lead to activation of p53-mediated growth suppression in human cells, indicating that p53 can function as a brake on PIP3-induced mitogenesis during human cancer pathogenesis. Experiment Overall Design: Two HCT116 PTEN+/+ cell lines (parental cells and a clone with random integration of the targeting vector) and three independently-derived HCT116 PTEN-/- cell lines were studied
2008-06-14 | E-GEOD-6263 | biostudies-arrayexpress
Project description:A wealth of proteogenomic data has been generated using cancer samples to deepen our understanding of the mechanisms of cancer and how biological networks are altered in association with somatic mutation of tumor suppressor genes, such as TP53 and PTEN. To generate functional signatures of TP53 or PTEN loss, we profiled the RNA and phosphoproteomes of the MCF10A epithelial cell line, along with its congenic TP53- or PTEN-knockout derivatives, upon perturbation with the monofunctional DNA alkylating agent methyl methanesulfonate (MMS) vs. mock-treatment. To enable quantitative and reproducible mass spectrometry data generation, the cell lines were SILAC-labeled (stable isotope labeling with amino acids in cell culture), and the experimental design included label swapping and biological replicates. All data are publicly available and may be used to advance our understanding of the TP53 and PTEN tumor suppressor genes and to provide functional signatures for bioinformatic analyses of proteogenomic datasets.
2023-11-20 | GSE171572 | GEO
Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN in the A375 melanoma cell line that harbors a BRAFV600E mutation. Kinome profiling was performed using the parental line and two PTEN KO clones (5 and 11), treated with DMSO, or treated with 100nM dabrafenib and 10nM trametinib for 1 day or for 7 days. PTEN KO cells showed dramatically increased binding of HER3 and AKT3 compared to wild type. The activation of the SOX10-FOXD3-HER3-AKT axis in PTEN KO cells could be targeted with the ERBB/HER inhibitor neratinib.
2024-04-23 | PXD033921 | Pride
Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN in the A375 melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing and functional kinome analysis revealed the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAFand MEK1/2 in PTEN null, BRAFV600E cells dramatically induced expression of ERBB3/HER3 relative to wild type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with inhibitors for mutant BRAF/MEK1/2 identified the pan ERBB/HER inhibitor, neratinib, as reversing the resistance observed in PTEN null, BRAFV600E cells. The findings indicate PTEN null BRAFV600E melanoma becomes dependent on ERBB/HER signaling when treated with clinically approved BRAF and MEK inhibitors. Future studies are warranted to test neratinib reversal of resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.
2024-04-23 | PXD033866 | Pride
Project description:The tumor stroma is believed to contribute to some of the most malignant characteristics of epithelial tumors. However, signaling between stromal and tumor cells is complex and remains poorly understood. Here we show that genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumors. Global gene expression profiling in mammary stromal cells identified a Pten-specific signature associated with massive extra-cellular matrix (ECM) remodeling, innate immune cell infiltraion and increased angiogenesis. Execution of this transcriptional program was mediated, in part, by the induction, phosphorylation and recruitment of Ets2 to target promoters. Remarkably, Ets2 inactivation in Pten stroma-deleted tumors was sufficient to decrease tumor growth and progression. These findings identify the Pten-Ets2 axis as a critical stroma-specific signaling pathway that suppresses mammary epithelial tumors. Experiment Overall Design: Wild type and Pten null primary mammary fibroblasts isolated from 8 week old female mice were cultured, RNA was extracted and Affymetrix gene expression arrays were performed.
2009-11-10 | E-GEOD-16073 | biostudies-arrayexpress
Project description:The tumor stroma is believed to contribute to some of the most malignant characteristics of epithelial tumors. However, signaling between stromal and tumor cells is complex and remains poorly understood. Here we show that genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumors. Global gene expression profiling in mammary stromal cells identified a Pten-specific signature associated with massive extra-cellular matrix (ECM) remodeling, innate immune cell infiltraion and increased angiogenesis. Execution of this transcriptional program was mediated, in part, by the induction, phosphorylation and recruitment of Ets2 to target promoters. Remarkably, Ets2 inactivation in Pten stroma-deleted tumors was sufficient to decrease tumor growth and progression. These findings identify the Pten-Ets2 axis as a critical stroma-specific signaling pathway that suppresses mammary epithelial tumors.
2009-10-22 | GSE16073 | GEO
Project description:While naive BMDMs without further treatment are referred to as M0-like macrophages, which can be polarized to either M1-like or M2-like macrophages,To assess the consequence of PTEN binding on macrophages, we profiled the global transcriptome of M0-like BMDMs with and without PTEN treatment.
2024-07-25 | GSE249264 | GEO
Project description:Decremental loss of PTEN results in cancer susceptibility and tumor progression. In turn this raises the possibility that PTEN elevation might be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with variably elevated PTEN expression levels, taking advantage of BAC (Bacterial Artificial Chromosome)-mediated transgenesis. Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake, increased mitochondrial oxidative phosphorylation, and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and independent pathways, and negatively impacts two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect. In order to elucidate the pathophysiological impact of PTEN elevation, we generated transgenic mice carrying additional copies of this critical tumor suppressor gene (referred to as Super-PTEN mice). In order to maintain the regulation properties of the endogenous Pten gene, we made use of large genomic fragments containing the entire Pten locus carried by BACs (Bacterial Artificial Chromosomes). We next generated mouse embryonic fibroblasts (MEFs) and confirmed successful overexpression of PTEN by the BAC transgenic system. Primary cells derived from Super-PTEN mice represent a powerful tool to elucidate the molecular mechanisms underlying dose-dependent PTEN actions. We therefore performed microarray analysis in primary cells (MEFs) derived from day 13.5 embryos obtained by crossing Super-PTEN mice with C57BL6 mice. Three independent embryos from each genotype were analyzed (background: >98%C57BL6 / CBA). Gene expression profile analysis in these cells will reveal target genes and pathways differentially regulated upon PTEN elevation.
2012-12-01 | E-GEOD-35670 | biostudies-arrayexpress
Project description:PTEN is one of the most frequently mutated tumor suppressor genes, its loss has been reported in multiple tumor types and is associated with a poor outcome. PTEN-L, as a secreted isoform of PTEN, with the ability to enter cells and inhibit tumor cell growth via inhibiting AKT mediated cell proliferation. However, the distinct effect of PTEN-L on PTEN-expression or PTEN-loss tumor cells is not known yet. Here, we identified PTEN-L treatment facilitate E0771-PTEN-null tumor cells, but not PTEN-wide-type tumor cells lung outgrowth. RNA-seq and Western blot analysis suggest PTEN-L stimulation induced PTEN-null tumor cells dormancy, namely, upregulation of dormancy markers p16 and p27, cell cycle arrest, reduced cell proliferation and chemotherapy drugs resistance. Further study suggested PTEN-L mediated p38 signaling activation play the major role for PTEN-null tumor cell dormancy. The p38 inhibitor, SB202190 significantly reversed the PTEN-L induced PTEN-null tumor cells dormancy and outgrowth in lungs. Further investigation indicated the dormant PTEN-null tumor cells could escape from immunosurveillance and thus outgrowth in lungs, as PTEN-L did not promote PTEN-null tumor cells outgrowth in lung of SCID mice. Therefore, we propose that PTEN-L protects PTEN-null tumor cells from immune attack during lung metastasis via activating dormancy related pathways. This study identified PTEN-L as an activator of PTEN-loss tumor cells dormancy, which enables the efficient seeding and outgrowth of tumor cells in metastatic niches. Overall, we highlight PTEN expression status decides the outcome of PTEN-L mediated anti-tumor therapy.
2024-05-17 | GSE246600 | GEO