Loss of the Aryl Hydrocarbon Receptor (AhR) Promotes Cancer Cells Resistance to BRAFV600E Targeted Therapies. [CRISPR]
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PROVIDER: PRJNA1207941 | ENA |
REPOSITORIES: ENA
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Project description:Predicting a patient’s response to chemotherapies and identifying additional molecular targets to improve treatment efficacy are major objectives in cancer research. BRAFV600E inhibitors targeting the MAP kinase pathway showed promising initial clinical results in thyroid cancers (TCs) for metastatic or recurrent tumors refractory to radioiodine treatments. BRAFV600E-targeted therapies have also been approved by the FDA for the treatment of some unresectable or metastatic BRAFV600E+ solid tumors. Still, for most patients, the response to BRAFV600E blocking therapy is transient due to cell proliferation reactivation through escape pathways. We performed a genome-wide CRISPR screen to reveal targets in TCs that facilitate resistance or sensitize thyroid cancer cells to inhibitors of the MAP kinase pathway. Among the genes that consistently altered MAPK inhibitor treatment response, we identified the Aryl hydrocarbon Receptor (AhR) and its molecular partner, the AhR nuclear translocator (ARNT). The AHR-ARNT heteroduplex is an environmental sensor that integrates extracellular, endogenous, and metabolic signals to equilibrate cell activity. Inactivation of AhR or ARNT increased TC cells' resistance to targeted therapies. Our study revealed that AhR-deficient cancer cells expressed elevated activity in genes linked to the TGFβ-mediated SMAD2/3 pathway after drug treatment. Our results suggest that SMAD2/3 competes to bind ARNT and that the loss of AhR gives cancer cells a potent escape pathway to targeted therapies, counteracting MAPK inhibition with SMAD activation to sustain cancer cell proliferation.
2025-01-12 | GSE286107 | GEO
Project description:Predicting a patient’s response to chemotherapies and identifying additional molecular targets to improve treatment efficacy are major objectives in cancer research. BRAFV600E inhibitors targeting the MAP kinase pathway showed promising initial clinical results in thyroid cancers (TCs) for metastatic or recurrent tumors refractory to radioiodine treatments. BRAFV600E-targeted therapies have also been approved by the FDA for the treatment of some unresectable or metastatic BRAFV600E+ solid tumors. Still, for most patients, the response to BRAFV600E blocking therapy is transient due to cell proliferation reactivation through escape pathways. We performed a genome-wide CRISPR screen to reveal targets in TCs that facilitate resistance or sensitize thyroid cancer cells to inhibitors of the MAP kinase pathway. Among the genes that consistently altered MAPK inhibitor treatment response, we identified the Aryl hydrocarbon Receptor (AhR) and its molecular partner, the AhR nuclear translocator (ARNT). The AHR-ARNT heteroduplex is an environmental sensor that integrates extracellular, endogenous, and metabolic signals to equilibrate cell activity. Inactivation of AhR or ARNT increased TC cells' resistance to targeted therapies. Our study revealed that AhR-deficient cancer cells expressed elevated activity in genes linked to the TGFβ-mediated SMAD2/3 pathway after drug treatment. Our results suggest that SMAD2/3 competes to bind ARNT and that the loss of AhR gives cancer cells a potent escape pathway to targeted therapies, counteracting MAPK inhibition with SMAD activation to sustain cancer cell proliferation.
2025-01-12 | GSE286108 | GEO
Project description:Loss of the Aryl Hydrocarbon Receptor (AhR) Promotes Cancer Cells Resistance to BRAFV600E Targeted Therapies. [RNA-Seq]
| PRJNA1207950 | ENA
Project description:As part of a study of the role of the aryl hydrocarbon receptor (Ahr) in maintenance and senescence of hematopoietic stem cells (HSC), global gene expression profiling was done with HSC isolated from Ahr-knockout and wild-type mice. HSC from young-adult (8 wk old) AhR-KO mice had changes in expression of many genes related to HSC maintenance, consistent with the phenotype observed in aging Ahr-KO mice: decreased survival rate, splenomegaly, increased circulating white blood cells, hematopoietic cell accumulation in tissues, anemia, increased numbers of stem/progenitor and lineage-committed cells in bone marrow, decreased erythroid progenitor cells in bone marrow, and decreased self-renewal capacity of HSC. 7 samples: 3 Ahr knockout, 4 wild-type
2013-11-08 | E-GEOD-46976 | biostudies-arrayexpress
Project description:As part of a study of the role of the aryl hydrocarbon receptor (Ahr) in maintenance and senescence of hematopoietic stem cells (HSC), global gene expression profiling was done with HSC isolated from 18-month-old Ahr-knockout and wild-type mice. HSC from aged AhR-KO mice had changes in expression of many genes related to HSC maintenance, consistent with the phenotype observed in aging Ahr-KO mice: decreased survival rate, splenomegaly, increased circulating white blood cells, hematopoietic cell accumulation in tissues, anemia, increased numbers of stem/progenitor and lineage-committed cells in bone marrow, decreased erythroid progenitor cells in bone marrow, and decreased self-renewal capacity of HSC. 10 samples: 5 Ahr knockout, 5 wild-type
2015-03-28 | E-GEOD-67378 | biostudies-arrayexpress
Project description:As part of a study of the role of the aryl hydrocarbon receptor (Ahr) in maintenance and senescence of hematopoietic stem cells (HSC), global gene expression profiling was done with HSC isolated from Ahr-knockout and wild-type mice. HSC from young-adult (8 wk old) AhR-KO mice had changes in expression of many genes related to HSC maintenance, consistent with the phenotype observed in aging Ahr-KO mice: decreased survival rate, splenomegaly, increased circulating white blood cells, hematopoietic cell accumulation in tissues, anemia, increased numbers of stem/progenitor and lineage-committed cells in bone marrow, decreased erythroid progenitor cells in bone marrow, and decreased self-renewal capacity of HSC.
2013-11-08 | GSE46976 | GEO
Project description:Disruption of the lung endothelial-epithelial cell barrier during respiratory virus infection causes cell and fluid accumulation in the air spaces and compromises vital gas exchange function. Endothelial cell dysfunction is known to exacerbate tissue damage; however, it is unclear whether the lung endothelium engages in tissue-protective activity during viral infection. Here we show that the environmental sensor aryl hydrocarbon receptor (AHR) is predominantly active in endothelial cells and protects against influenza-induced lung damage. Endothelial-specific AHR deletion caused increased vascular leakage in air spaces and enhanced influenza-induced lung tissue pathology. Global expression profiling revealed limited AHR-dependent regulation of vessels in the steady-state lung. However, following influenza-induced tissue damage and inflammation, AHR engages tissue-protective programmes in endothelia and prevents a dysplastic keratinised and apoptotic signature in the airways of infected lungs.
2023-05-23 | GSE203427 | GEO
Project description:Acinetobacter baumannii is a highly pathogenic and multidrug-resistant Gram-negative bacterium that causes severe nosocomial infections. To better understand the mechanism of pathogenesis, we compare the proteomes of uninfected and infected human cells, revealing that transcription factor FOS is the host protein most strongly induced by A. baumannii infection. Pharmacological inhibition of FOS reduces the cytotoxicity of A. baumannii in cell-based models, and similar results are also observed in a mouse infection model. A. baumannii outer membrane vesicles (OMVs) are shown to activate the aryl hydrocarbon receptor (AHR) of host cells by inducing the host enzyme tryptophan-2,3-dioxygenase (TDO), producing the ligand kynurenine, which binds AHR. Following ligand binding, AHR is a direct transcriptional activator of the FOS gene. Our results suggest that bacterial infection interacts with host tryptophan metabolism and the transcription factor FOS.
2024-08-05 | PXD053768 | Pride
Project description:As part of a study of the role of the aryl hydrocarbon receptor (Ahr) in maintenance and senescence of hematopoietic stem cells (HSC), global gene expression profiling was done with HSC isolated from bone marrow restricted conditional Ahr-knockout and AhR floxed mice. HSC from young-adult (8 wk old) cAhR-KO mice had changes in expression of many genes related to HSC maintenance, consistent with the phenotype observed in Ahr-KO mice. Aged cAhR-KO mice (18 months old) also displayed alterations in peripheral white blood cell counts, serial repopulation potential and levels of ROS in bone marrow cells, consistent with previous observations on the role of AhR in the hematopoietic system. 22 samples: 5 young Ahr knockout, 6 old Ahr knockout, 5 young floxed Ahr, 6 old floxed Ahr
2016-06-30 | E-GEOD-76276 | biostudies-arrayexpress
Project description:[original Title] Comparison of expression data of primary murine melanocytes from aryl hydrocarbon deficient mice and corresponding wild-type C57BL/6 mice Melanin is produced exclusively by melanocytes and melanogenesis is the vital response to protect skin cells against Ultraviolet B (UVB)-induced DNA damage. The aryl hydrocarbon receptor (AhR) is a transcription factor, which may be involved in the physiological tanning response. Normal murine melanocytes express functional AhR. We tested gene expression in WT versus AhR-deficient mice primary murine melanocytes, isolated from the skin and cultivated for several passages. Skin epidermal cells from 2 individual C57BL/6 mice and 2 individual AhR-deficient mice (deletion of exon2, AhRtm1Bra) were grown for 6-8 weeks in selection medium to propagate melanocytes.
2010-09-05 | E-GEOD-19411 | biostudies-arrayexpress