Effective reprogramming of patient-derived M2-polarized glioblastoma-associated microglia/macrophages by treatment with GW2580
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001007466 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor in adults, can be divided into several molecular subtypes including proneural GBM. Most clinical strategies aimed at directly targeting glioma cells in these tumors have failed. A promising alternative is to target stromal cells in the brain microenvironment, such as tumor-associated microglia and macrophages (TAMs). Macrophages are dependent upon colony stimulating factor (CSF)-1 for differentiation and survival; therefore, we used an inhibitor of its receptor, CSF-1R, to target macrophages in a mouse proneural GBM model. CSF-1R inhibition dramatically increased survival in mice and regressed established GBMs. Tumor cell apoptosis was significantly increased, and proliferation and tumor grade markedly decreased. Surprisingly, TAMs were not depleted in tumors treated with the CSF-1R inhibitor. Instead, analysis of gene expression in TAMs isolated from treated tumors revealed a decrease in alternatively activated/ M2 macrophage markers, consistent with impaired tumor-promoting functions. These gene signatures were also associated with better survival specifically in the proneural subtype of patient gliomas. Collectively, these results establish macrophages as valid therapeutic targets in proneural gliomas, and highlight the clinical potential for CSF-1R inhibitors in GBM. RNA was isolated from sorted tumor associated macrophages (TAMs) from murine gliomas following either 7 days of vehicle or BLZ945 treatment. Samples were collected from 16 total tumor burdened mice, with 8 replicates for each treatment group. BLZ945: a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor
2013-09-20 | E-GEOD-37475 | biostudies-arrayexpress
Project description:Pre- and post-treatment tumor biopsies from 8 patient with metastatic uveal melanoma patients were analysed by single cell RNAseq. Transcriptomic profiling of myeloid populations including macrophages, monocytes, and dendritic cells was carried out. M2 macrophage subsets were identified at baseline and treatment-induced M2 to M1 macrophage reprogramming was characterised.
2025-02-05 | GSE287090 | GEO
Project description:Diet-induced obesity is reported to induce a phenotypic switch in adipose tissue macrophages from an antiinflammatory M2 state to a proinflammatory M1 state. Telmisartan, an angiotensin II type 1 receptor antagonist and a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, reportedly has beneficial effects on insulin sensitivity. We studied the effects of telmisartan on the adipose tissue macrophage phenotype in high fat-fed mice. Telmisartan was administered for 5 weeks to high fat-fed C57BL/6 mice. Insulin sensitivity, macrophage infiltration, and the gene expressions of M1 and M2 markers in epididymal fat tissues were examined. Insulin- or a glucose-tolerance test showed that telmisartan treatment improved insulin resistance, decreasing the body weight gain, visceral fat weight and adipocyte size without affecting the amount of food intake. Telmisartan treatment reduced the number of CD11c-positive cells and crown-like structures. Telmisartan reduced the mRNA expressions of M1 macrophage markers, such as TNF-alpha and IL-6, and increased the expression of M2 markers, such as IL-10 and Mgl2. The reduction of M1 macrophage markers, as well as the increased gene expression of M2 markers especially IL-10, is a possible mechanism for the improvement of insulin sensitivity by telmisartan.
2010-01-23 | GSE19954 | GEO
Project description:Glioblastoma, the most aggressive primary brain cancer, has dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we here systematically screen repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling >2,500 ex vivo drug responses across 27 patients and 132 drugs identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems. Interpretable molecular machine learning of drug-target networks revealed neuroactive convergence on AP-1/BTG-driven glioblastoma suppression, enabling expanded in silico screening of >1 million compounds with high patient validation accuracy. Deep multi-modal profiling confirmed Ca2+-driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the antidepressant Vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology.
| MSV000090357 | MassIVE
Project description:Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor. The brain-infiltrative character of glioblastoma makes complete surgical removal of the tumor impossible and neither radiation nor current chemotherapy provide cure. Recent evidence shows that glioblastoma multiforme consists of heterogeneous cell populations which differ in tumor-forming potential. Enriched tumor-initiating capacity has been linked to poorly differentiated glioblastoma cells sharing features with neural stem cells. Thus, these cells are important targets for new therapeutic strategies. We aim to identify novel targets controlling maintenance and differentiation in glioblastoma-initiating cells through high throughput screening. To this end, we utilized libraries of small chemical compounds and small interference RNAs in combination with automated imaging and data analysis. Patient-derived glioblastoma cells were expanded and characterized using neural stem cell conditions. In culture, the cells showed low differentiation but expression of neural stem cell markers such as Nestin and Sox2. Upon intracranial injection into SCID mice these cells gave rise to tumors displaying the hallmarks of the human disease. Differentiation of glioblastoma-initiating cells (for example elicited through bone morphogenetic protein, BMP) was associated with strong morphological changes. Hence, cellular morphology, as well as markers specific for differentiation or death were used as screen readout. Lentiviral RNA interference-based screening yielded several gene knockdowns leading to ‘forced’ differentiation of glioblastoma-initiating cells. For example, knockdown of TRRAP (transformation/transcription domain associated protein) led to strongly increased differentiation and loss of proliferative and self-renewing capacity in these cells. TRRAP is an adapter protein implicated in oncogenic transformation through c-MYC transcription activation, also participating in chromatin remodeling and DNA repair. Glioblastoma-initiating cells with reduced TRRAP displayed increased apoptosis upon treatment with the genotoxic agent temozolomide. In vivo, Trapp knockdown cells were not able to give rise to glioblastoma upon transplantation into the brain of SCID mice. Together, these findings support a crucial role for TRRAP in maintenance and tumorigenicity of glioblastoma-initiating cells and might offer future therapeutic options. Two treatments compared to control: two different shRNA sequences for TRRAP were compared to a control shRNA sequence in their effects on global transcription in brain tumor initiating cells
2011-03-14 | E-GEOD-27931 | biostudies-arrayexpress
Project description:GM-CSF paradoxically possesses ability to differentiate both classically activated macrophages (MØs) with dominant proinflammatory function (M1-like MØs) and alternative activated MØs with strong immunosuppressive function (M2-like MØs). The intrinsic regulatory mechanism responsible for functional polarization of MØs under GM-CSF signalling remains elusive. Here we revealed that cytokine-inducible SH2-containing protein (CIS), induced by GM-CSF, is a key determinant in controlling MØ polarization. Compared to WT MØs, Cish-/- MØs gained characteristics of alternative activated MØs (M2 MØs), showing high expression of prototypic M2 markers Arginase 1, Tgm2 and YM-1; strong suppression of T cell proliferation; and low production of IL-12 and other proinflammatory cytokines¬¬. Differing from canonical IL-4/STAT6/IRF4 signaling axis of M2 induction, development of M2 MØ characteristics in Cish-/- MØs was associated with intensified STAT5 activation and consequent IRF8 downregulation. Attenuation of GM-CSF signalling via JAK inhibition and IRF8 rescue corrected certain functional defects in Cish-/- MØs. As CIS inhibition in NK and T cells promotes anti-tumour immunity, we showed that CIS deficiency enhanced the development of intra-tumoural M2 MØs and reduced CTL induction within tumour microenvironment with elevated GM-CSF. Overall, we conclude that CIS acts as an intrinsic rheostat to control intense GM-CSF signalling in order to maintain proinflammatory functions of MØs. Targeting CIS as a checkpoint in cancer immunotherapy should consider its role in regulating myeloid cell function.
2023-01-21 | PXD018390 | Pride
Project description:Dwivedi2014 - Healthy Volunteer IL6
Model
This model is comprised of four models:
[BIOMD0000000534]
Healthy Volunteer model
[BIOMD0000000535]
Crohn's Disease - IL-6 Antibody
[BIOMD0000000536]
Crohn's Disease - sgp130FC
[BIOMD0000000537]
Crohn's Disease - IL-6Ra Antibody
Possible avenues for Interleukin-6 (IL-6) inhibition in
treating Crohn's disease are compared here. Each model refers to
separate ligands. The system simulates differential activity of the
ligands on the signalling of IL-6.
This affects Signal Transducer and Activator of
Transcription 3 (STAT3) activity on the production of
biomarker C-Reactive Protein (CRP) expression.
Figures referring to this Healthy Volunteer model are 2c and
2d.
This model is described in the article:
A multiscale model of
interleukin-6-mediated immune regulation in Crohn's disease and
its application in drug discovery and development.
Dwivedi G, Fitz L, Hegen M, Martin
SW, Harrold J, Heatherington A, Li C.
CPT Pharmacometrics Syst Pharmacol
2014; 3: e89
Abstract:
In this study, we have developed a multiscale systems model
of interleukin (IL)-6-mediated immune regulation in Crohn's
disease, by integrating intracellular signaling with
organ-level dynamics of pharmacological markers underlying the
disease. This model was linked to a general pharmacokinetic
model for therapeutic monoclonal antibodies and used to
comparatively study various biotherapeutic strategies targeting
IL-6-mediated signaling in Crohn's disease. Our work
illustrates techniques to develop mechanistic models of disease
biology to study drug-system interaction. Despite a sparse
training data set, predictions of the model were qualitatively
validated by clinical biomarker data from a pilot trial with
tocilizumab. Model-based analysis suggests that strategies
targeting IL-6, IL-6R?, or the IL-6/sIL-6R? complex are less
effective at suppressing pharmacological markers of Crohn's
than dual targeting the IL-6/sIL-6R? complex in addition to
IL-6 or IL-6R?. The potential value of multiscale system
pharmacology modeling in drug discovery and development is also
discussed.CPT: Pharmacometrics & Systems Pharmacology
(2014) 3, e89; doi:10.1038/psp.2013.64; advance online
publication 8 January 2014.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000534.
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.
2024-09-02 | BIOMD0000000534 | BioModels
Project description:Dwivedi2014 - Crohns IL6 Disease model -
Anti-IL6 Antibody
This model is comprised of four models:
[BIOMD0000000534]
Healthy Volunteer model
[BIOMD0000000535]
Crohn's Disease - IL-6 Antibody
[BIOMD0000000536]
Crohn's Disease - sgp130FC
[BIOMD0000000537]
Crohn's Disease - IL-6Ra Antibody
Possible avenues for Interleukin-6 (IL-6) inhibition in
treating Crohn's disease are compared here. Each model refers to
separate ligands. The system simulates differential activity of the
ligands on the signalling of IL-6.
This affects Signal Transducer and Activator of
Transcription 3 (STAT3) activity on the production of
biomarker C-Reactive Protein (CRP) expression.
Figures referring to this Crohn's Disease model are 4a, 4b,
4c and 5a.
This model is described in the article:
A multiscale model of
interleukin-6-mediated immune regulation in Crohn's disease and
its application in drug discovery and development.
Dwivedi G, Fitz L, Hegen M, Martin
SW, Harrold J, Heatherington A, Li C.
CPT Pharmacometrics Syst Pharmacol
2014; 3: e89
Abstract:
In this study, we have developed a multiscale systems model
of interleukin (IL)-6-mediated immune regulation in Crohn's
disease, by integrating intracellular signaling with
organ-level dynamics of pharmacological markers underlying the
disease. This model was linked to a general pharmacokinetic
model for therapeutic monoclonal antibodies and used to
comparatively study various biotherapeutic strategies targeting
IL-6-mediated signaling in Crohn's disease. Our work
illustrates techniques to develop mechanistic models of disease
biology to study drug-system interaction. Despite a sparse
training data set, predictions of the model were qualitatively
validated by clinical biomarker data from a pilot trial with
tocilizumab. Model-based analysis suggests that strategies
targeting IL-6, IL-6R?, or the IL-6/sIL-6R? complex are less
effective at suppressing pharmacological markers of Crohn's
than dual targeting the IL-6/sIL-6R? complex in addition to
IL-6 or IL-6R?. The potential value of multiscale system
pharmacology modeling in drug discovery and development is also
discussed.CPT: Pharmacometrics & Systems Pharmacology
(2014) 3, e89; doi:10.1038/psp.2013.64; advance online
publication 8 January 2014.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000535.
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.
2024-09-02 | BIOMD0000000535 | BioModels
Project description:Dwivedi2014 - Crohns IL6 Disease model -
Anti-IL6R Antibody
This model is comprised of four models:
[BIOMD0000000534]
Healthy Volunteer model
[BIOMD0000000535]
Crohn's Disease - IL-6 Antibody
[BIOMD0000000536]
Crohn's Disease - sgp130FC
[BIOMD0000000537]
Crohn's Disease - IL-6Ra Antibody
Possible avenues for Interleukin-6 (IL-6) inhibition in
treating Crohn's disease are compared here. Each model refers to
separate ligands. The system simulates differential activity of the
ligands on the signalling of IL-6.
This affects Signal Transducer and Activator of
Transcription 3 (STAT3) activity on the production of
biomarker C-Reactive Protein (CRP) expression.
Figures referring to this Crohn's Disease model are 3a, 4d,
4e, 4f and 5b.
This model is described in the article:
A multiscale model of
interleukin-6-mediated immune regulation in Crohn's disease and
its application in drug discovery and development.
Dwivedi G, Fitz L, Hegen M, Martin
SW, Harrold J, Heatherington A, Li C.
CPT Pharmacometrics Syst Pharmacol
2014; 3: e89
Abstract:
In this study, we have developed a multiscale systems model
of interleukin (IL)-6-mediated immune regulation in Crohn's
disease, by integrating intracellular signaling with
organ-level dynamics of pharmacological markers underlying the
disease. This model was linked to a general pharmacokinetic
model for therapeutic monoclonal antibodies and used to
comparatively study various biotherapeutic strategies targeting
IL-6-mediated signaling in Crohn's disease. Our work
illustrates techniques to develop mechanistic models of disease
biology to study drug-system interaction. Despite a sparse
training data set, predictions of the model were qualitatively
validated by clinical biomarker data from a pilot trial with
tocilizumab. Model-based analysis suggests that strategies
targeting IL-6, IL-6R?, or the IL-6/sIL-6R? complex are less
effective at suppressing pharmacological markers of Crohn's
than dual targeting the IL-6/sIL-6R? complex in addition to
IL-6 or IL-6R?. The potential value of multiscale system
pharmacology modeling in drug discovery and development is also
discussed.CPT: Pharmacometrics & Systems Pharmacology
(2014) 3, e89; doi:10.1038/psp.2013.64; advance online
publication 8 January 2014.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000537.
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.
2024-09-02 | BIOMD0000000537 | BioModels
Project description:Dwivedi2014 - Crohns IL6 Disease model -
sgp130 activity
This model is comprised of four models:
[BIOMD0000000534]
Healthy Volunteer model
[BIOMD0000000535]
Crohn's Disease - IL-6 Antibody
[BIOMD0000000536]
Crohn's Disease - sgp130FC
[BIOMD0000000537]
Crohn's Disease - IL-6Ra Antibody
Possible avenues for Interleukin-6 (IL-6) inhibition in
treating Crohn's disease are compared here. Each model refers to
separate ligands. The system simulates differential activity of the
ligands on the signalling of IL-6.
This affects Signal Transducer and Activator of
Transcription 3 (STAT3) activity on the production of
biomarker C-Reactive Protein (CRP) expression.
The figure referring to this Crohn's Disease model is 6b.
This model is described in the article:
A multiscale model of
interleukin-6-mediated immune regulation in Crohn's disease and
its application in drug discovery and development.
Dwivedi G, Fitz L, Hegen M, Martin
SW, Harrold J, Heatherington A, Li C.
CPT Pharmacometrics Syst Pharmacol
2014; 3: e89
Abstract:
In this study, we have developed a multiscale systems model
of interleukin (IL)-6-mediated immune regulation in Crohn's
disease, by integrating intracellular signaling with
organ-level dynamics of pharmacological markers underlying the
disease. This model was linked to a general pharmacokinetic
model for therapeutic monoclonal antibodies and used to
comparatively study various biotherapeutic strategies targeting
IL-6-mediated signaling in Crohn's disease. Our work
illustrates techniques to develop mechanistic models of disease
biology to study drug-system interaction. Despite a sparse
training data set, predictions of the model were qualitatively
validated by clinical biomarker data from a pilot trial with
tocilizumab. Model-based analysis suggests that strategies
targeting IL-6, IL-6R?, or the IL-6/sIL-6R? complex are less
effective at suppressing pharmacological markers of Crohn's
than dual targeting the IL-6/sIL-6R? complex in addition to
IL-6 or IL-6R?. The potential value of multiscale system
pharmacology modeling in drug discovery and development is also
discussed.CPT: Pharmacometrics & Systems Pharmacology
(2014) 3, e89; doi:10.1038/psp.2013.64; advance online
publication 8 January 2014.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000536.
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.
2024-09-02 | BIOMD0000000536 | BioModels