Gene expression profiling of GSK3 inhibitor (CHIR99021)-treated intestinal organoids
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE110257 | GEO | 2018/02/08
REPOSITORIES: GEO
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Project description:EGF and HRG, growth factor ligands for EGFR and ErbB3/4 receptor, induce transient and sustained ERK activity associated with cellular proliferation and differentiation of MCF-7 cells, respectively. To rigorously analyze the effect of ERK signal duration for mRNA expression dynamics and its relationship with cell determination, we modified the EGF-triggered ERK signal duration by changing the EGFR activation dynamics by impairing the ubiquitination and degradation process. Mutation of the six lysine residues (6KR; K692, K713, K730, K843, K905 and K946) of the EGFR responsible for ubiquitin conjugation has shown sustained phosphorylation of the receptor (Huang et al, 2006; Goh et al, 2010). Therefore we constructed the MCF-7 cell lines that stably express 6KR EGFR (6KR), and analyzed signaling and mRNA expression dynamics in response to EGF and HRG.
2014-12-01 | GSE57547 | GEO
Project description:The EGFR/Ras/ERK signalling pathway is a primary driver of cancer cell proliferation and metastasis in tumours that exhibit high cell-to-cell heterogeneity. While the signalling activity of this pathway is frequently amplified in tumours, it is not understood how the kinetic aspects of its activation in tumours differ from normal cellular signalling. We explored these single-cell kinetic differences using live-cell reporters of ERK signalling in the breast cancer progression series HMT-3522 and found that ERK activity in invasive cells is similar in amplitude to non-malignant cells but is highly dynamic and more disordered, leading to more heterogeneous expression of ERK target genes. We traced this variability to a high degree of amphiregulin-mediated autocrine signalling by invasive cells. Dynamic ERK activity could be transferred from invasive to pre-malignant cells through paracrine signalling in co-culture, and could drive temporal variation in the expression of genes including Fra-1, c-Myc, and Egr1 at the single-cell level. Our findings establish a mechanism for the generation of tumour cell plasticity, in which paracrine signalling in the microenvironment is translated into continually shifting diversity in gene expression profiles, helping drive the phenotypic heterogeneity of tumour cells.
2020-08-01 | GSE118312 | GEO
Project description:Orton2009 - Modelling cancerous mutations in
the EGFR/ERK pathway - EGF Model
This model studies the aberrations in
ERK signalling for different cancer mutations. The authors alter a
previously existing EGF model (Brown et al 2004) to include new
interactions that better fit empirical data.
Predictions show that the ERK signalling is a robust mechanism
taking different courses for different cancer mutations. Most
parameter values are used from the previous model and the new
parameters are estimated using experimental data performed by
the authors on PC12 cells (adrenal gland, rat). The authors
provide an SBML version of the model in the paper.
This model is described in the article:
Computational
modelling of cancerous mutations in the EGFR/ERK signalling
pathway.
Orton RJ, Adriaens ME, Gormand A,
Sturm OE, Kolch W, Gilbert DR.
BMC Syst Biol 2009 Oct; 3: 100
Abstract:
The Epidermal Growth Factor Receptor (EGFR) activated
Extracellular-signal Regulated Kinase (ERK) pathway is a
critical cell signalling pathway that relays the signal for a
cell to proliferate from the plasma membrane to the nucleus.
Deregulation of the EGFR/ERK pathway due to alterations
affecting the expression or function of a number of pathway
components has long been associated with numerous forms of
cancer. Under normal conditions, Epidermal Growth Factor (EGF)
stimulates a rapid but transient activation of ERK as the
signal is rapidly shutdown. Whereas, under cancerous mutation
conditions the ERK signal cannot be shutdown and is sustained
resulting in the constitutive activation of ERK and continual
cell proliferation. In this study, we have used computational
modelling techniques to investigate what effects various
cancerous alterations have on the signalling flow through the
ERK pathway.We have generated a new model of the EGFR activated
ERK pathway, which was verified by our own experimental data.
We then altered our model to represent various cancerous
situations such as Ras, B-Raf and EGFR mutations, as well as
EGFR overexpression. Analysis of the models showed that
different cancerous situations resulted in different signalling
patterns through the ERK pathway, especially when compared to
the normal EGF signal pattern. Our model predicts that
cancerous EGFR mutation and overexpression signals almost
exclusively via the Rap1 pathway, predicting that this pathway
is the best target for drugs. Furthermore, our model also
highlights the importance of receptor degradation in normal and
cancerous EGFR signalling, and suggests that receptor
degradation is a key difference between the signalling from the
EGF and Nerve Growth Factor (NGF) receptors.Our results suggest
that different routes to ERK activation are being utilised in
different cancerous situations which therefore has interesting
implications for drug selection strategies. We also conducted a
comparison of the critical differences between signalling from
different growth factor receptors (namely EGFR, mutated EGFR,
NGF, and Insulin) with our results suggesting the difference
between the systems are large scale and can be attributed to
the presence/absence of entire pathways rather than subtle
difference in individual rate constants between the
systems.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000623.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2016-11-28 | BIOMD0000000623 | BioModels
Project description:The mechanisms of ErbB2 signalling and the effects of its overexpression are not fully understood. Herein, SILAC expression profiling and phosphopeptide enrichment of a relevant, non-transformed, immortalized human mammary luminal epithelial cell model were used to profile ErbB2-dependent differences in protein expression and phosphorylation events triggered via EGFR (EGF treatment) and ErbB3 (HRGbeta1 treatment) in the context of ErbB2 overexpression. Bioinformatics analysis was used to infer changes in cellular processes and signalling events. We demonstrate the complexity of the responses to oncogene expression and growth factor signalling and identify protein changes relevant to ErbB2-dependent altered cellular phenotype, in particular cell cycle progression and hyper-proliferation, reduced adhesion and enhanced motility. Numerous novel sites of growth factor-regulated phosphorylation were also identified that were enhanced by ErbB2 overexpression and we putatively link these to altered cell behaviour. Moreover, we have defined a novel mechanism by which ErbB signalling suppresses basal interferon signalling that would promote the survival and proliferation of mammary luminal epithelial cells.
2018-10-26 | PXD004195 | Pride
Project description:Osteoblast-induced EGFR/ERBB2 signaling in androgen-sensitive prostate carcinoma cells characterized by multiplex kinase activity profiling
2009-04-02 | E-TABM-626 | biostudies-arrayexpress
Project description:Bidkhori2012 - EGFR signalling in NSCLC
The paper describes and compares two models on EGFR signalling between normal and NSCLC cells. Moreover, it is shown that ERK (MAPK), STAT and Akt factor's activation pattern are different between normal and NSCLA models. This model corresponds to EGFR signalling in NSCLA cells.
Created by The MathWorks, Inc. SimBiology tool, Version 3.3
This model is described in the article:
Modeling of tumor progression in NSCLC and intrinsic resistance to TKI in loss of PTEN expression.
Bidkhori G, Moeini A, Masoudi-Nejad A
PloS one [2012, 7(10):e48004]
Abstract:
EGFR signaling plays a very important role in NSCLC. It activates Ras/ERK, PI3K/Akt and STAT activation pathways. These are the main pathways for cell proliferation and survival. We have developed two mathematical models to relate to the different EGFR signaling in NSCLC and normal cells in the presence or absence of EGFR and PTEN mutations. The dynamics of downstream signaling pathways vary in the disease state and activation of some factors can be indicative of drug resistance. Our simulation denotes the effect of EGFR mutations and increased expression of certain factors in NSCLC EGFR signaling on each of the three pathways where levels of pERK, pSTAT and pAkt are increased. Over activation of ERK, Akt and STAT3 which are the main cell proliferation and survival factors act as promoting factors for tumor progression in NSCLC. In case of loss of PTEN, Akt activity level is considerably increased. Our simulation results show that in the presence of erlotinib, downstream factors i.e. pAkt, pSTAT3 and pERK are inhibited. However, in case of loss of PTEN expression in the presence of erlotinib, pAkt level would not decrease which demonstrates that these cells are resistant to erlotinib.
This model is hosted on BioModels Database
and identified
by: MODEL1304020001
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2013-05-13 | BIOMD0000000453 | BioModels
Project description:Bidkhori2012 - normal EGFR signalling
The paper describes and compares two models on EGFR signalling between normal and NSCLC cells. Moreover, it is shown that ERK (MAPK), STAT and Akt factor's activation pattern are different between normal and NSCLA models. This model corresponds to EGFR signalling in normal cells.
Created by The MathWorks, Inc. SimBiology tool, Version 3.3
This model is described in the article:
Modeling of tumor progression in NSCLC and intrinsic resistance to TKI in loss of PTEN expression.
Bidkhori G, Moeini A, Masoudi-Nejad A
PloS one [2012, 7(10):e48004]
Abstract:
EGFR signaling plays a very important role in NSCLC. It activates Ras/ERK, PI3K/Akt and STAT activation pathways. These are the main pathways for cell proliferation and survival. We have developed two mathematical models to relate to the different EGFR signaling in NSCLC and normal cells in the presence or absence of EGFR and PTEN mutations. The dynamics of downstream signaling pathways vary in the disease state and activation of some factors can be indicative of drug resistance. Our simulation denotes the effect of EGFR mutations and increased expression of certain factors in NSCLC EGFR signaling on each of the three pathways where levels of pERK, pSTAT and pAkt are increased. Over activation of ERK, Akt and STAT3 which are the main cell proliferation and survival factors act as promoting factors for tumor progression in NSCLC. In case of loss of PTEN, Akt activity level is considerably increased. Our simulation results show that in the presence of erlotinib, downstream factors i.e. pAkt, pSTAT3 and pERK are inhibited. However, in case of loss of PTEN expression in the presence of erlotinib, pAkt level would not decrease which demonstrates that these cells are resistant to erlotinib.
This model is hosted on BioModels Database
and identified
by: MODEL1304020000
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2013-05-13 | BIOMD0000000452 | BioModels
Project description:FGF-MEK-ERK pathway has been implicated in diverse contexts in development. The pathway involves many autoinhibitory loops, resulting in pulse-like activity patterns. Here, we modulated the ERK activity during cardiac differentiation at the lateral plate mesoderm stage by PD0325901, a potent inhibitor of MEK, which is an upstream effector of ERK. We collected the resulting cell population, both in 2D and 3D, after cardiac specification to analyse how the ERK inhibition during induction affects the cell fate choice.
2023-06-30 | E-MTAB-12573 | biostudies-arrayexpress
Project description:Controlled activation of epidermal growth factor receptor (EGFR) is systematically guaranteed at the molecular level, however aberrant activation of EGFR is frequently found in cancer. Transcription induced by EGFR activation often involves coordinated expression of genes that positively and negatively regulate the original signaling pathway, therefore alterations in EGFR kinase activity may reflect changes in gene expression associated with the pathway. In this study, we investigated transcriptional changes following EGF stimulation with or without the EGFR kinase inhibitor Iressa in H1299 human non-small-cell lung cancer cells (parental H1299, H1299 cells which overexpress wild-type: EGFR-WT and mutant EGFR: L858R). Our results clearly showed differences in transcriptional activity in the absence or presence of EGFR kinase activity, and genes sharing the same molecular functions showed distinct expression dynamics. The results showed particular enrichment of EGFR/ErbB signaling-related genes in a differentially expressed gene set, and significant protein expression of MIG6/RALT(ERRFI1), an EGFR negative regulator, was confirmed in L858R. High MIG6 protein expression was correlated with basal EGFR phosphorylation and inversely correlated with EGF-induced ERK phosphorylation levels. Investigation of NCI-60 cell lines showed that ERRFI1 expression was correlated with EGFR expression regardless of tissue type. These results suggest that cells accumulate MIG6 as an inherent negative regulator to suppress excess EGFR activity when basal EGFR kinase activity is considerably high. Taken together, an EGFR mutation can cause transcriptional changes to accommodate the activation potency of the original signaling pathway at the cellular level. Experiment Overall Design: H1299 human non-small cell lung cancer cells were stimulated by the growth hormone (epidermal growth factor (EGF)) or EGFR kinase inhibitor (Iressa). Control was set as non-treated cells.
2009-08-09 | E-GEOD-11729 | biostudies-arrayexpress
Project description:Purpose: The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. The development of new and effective treatment has been and continues to be a major public health imperative. Methods: We report mutational and copy number analysis of 44 predominantly early-staged gallbladder tumors and 5-gallbladder cancer cell lines by a combination of directed and whole exome sequencing at an average coverage of 100X and above. Using gallbladder cancer cell lines and xenograft mouse models we performed phospho-proteome array profiling, followed by an in-depth functional characterization. Results: We describe recurrent activating ERBB2 somatic mutation in 6 of 44 gallbladder primary tumors with an overall mutation frequency of 13%, along with KRAS activating mutations in 3 of 44 samples. Consistent with whole exome findings, a phospho-proteomic array profile of 49-tyrosine kinase revealed constitutive phosphorylation of ERBB2 and EGFR that were found to heterodimerize. We demonstrate that treatment with ERBB2-specific, EGFR-specific shRNA or with covalent EGFR family inhibitor BIBW-2992 inhibits transformation, survival, migration, invasion, and tumor forming characteristics of gallbladder cancer cells harboring wild type or KRAS (G13D) but not KRAS (G12V) mutation. Furthermore, we show in vivo reduction in tumor size is paralleled by a reduction in the amounts of phospho-ERK in KRAS (G13D) but not in KRAS (G12V) xenografts, validating the in vitro findings Conclusion: Findings from this study implicate ERBB2 as an important therapeutic target in early stage gallbladder cancer. We also present the first evidence that the presence of KRAS (G12V), but not KRAS (G13D) mutation, may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to the clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer.
2018-12-29 | E-MTAB-6619 | biostudies-arrayexpress