Targeting EGFR to reverse PFOA-induced paradoxical hepatic lipotoxicity and cachexia-like phenotype-PRM
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Biran Zhu
PROVIDER: PXD081844 | iProX | Wed Jul 29 00:00:00 GMT+01:00 2026
REPOSITORIES: iProX
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Project description:Perfluorooctanoic acid (PFOA) is linked to metabolic disease, yet its impact on hepatic metabolism remains unclear. We exposed Western diet-fed mice to environmentally relevant PFOA and found that it did not cause classical hepatic steatosis. Instead, PFOA produced a cachexia-like phenotype, with peripheral fat loss, hepatomegaly, liver injury, and systemic inflammation, together with a paradoxical lipid response in which circulating lipids and hepatic lipid droplets fell while hepatic cholesterol rose. By combining metabolomics, 4D-DIA proteomics, network toxicology, and deep-learning, we identified EGFR as a shared target of PFOA and naringenin (NAR). PFOA bound EGFR, hyperactivating EGFR-STAT3 signaling to accelerate fatty acid oxidation and SREBP2-driven cholesterol biosynthesis, while inflammation suppressed HSD11B2 and raised corticosterone. NAR engaged the same target, restrained this signaling, and reversed metabolic dysregulation and inflammation while restoring HSD11B2. Ultimately, PFOA hepatotoxicity is not driven by steatosis and identify EGFR as a candidate target in pollutant-associated metabolic disease.
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Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET. Gene expression profiles were measured in 124 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EGFR-mutation gene expression signature trained in chemo-naive lung adenocarcinoma. The signature was computed as an index, called EGFR index.
2014-06-01 | E-GEOD-31852 | biostudies-arrayexpress
Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET.
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Project description:Quantification of EGFR complex component from Formaldehyde cross-linked immuno-purification using PRM method
2018-08-08 | MSV000082800 | MassIVE
Project description:Epidermal growth factor receptor (EGFR) is mostly known for its proliferative role in liver. Our earlier investigations indicated a paradoxical cell-death promoting facet of EGFR in acetaminophen (APAP)-induced liver injury (AILI) model. The current study investigates this unexpected role of EGFR in promoting AILI using a hepatocyte-specific EGFR deletion mouse model. Hepatocyte-specific EGFR-deficient mice were generated by administering AAV8-TBG-CRE in EGFRfl/fl mice and were subsequently treated with a severely toxic dose (500 mg/kg) of APAP. Liver injury, regeneration and associated signaling pathways were assessed at different time intervals. EGFR deletion significantly attenuated the progression of liver injury (beyond 12hr post-APAP) without altering early liver injury (up to 6 hr) following APAP overdose. Consistently, the key injury initiating events such as APAP-protein adducts formation and early JNK activation remained intact in EGFR-deficient mice. However, EGFR deletion restricted prolonged JNK activation and its mitochondrial translocation, resulting in reduced propagation of mitochondrial damage and release of cell death drivers. Further, the replenishment of antioxidant glutathione (GSH), which is known to limit the progression of liver injury, was strikingly faster in EGFR-deficient mice. RNA-seq analysis and consequent validation revealed marked upregulation of autophagy and its transcriptional regulator TFEB, a key response to remove damaged mitochondria, in EGFR-deficient mice. Paradoxically, EGFR deletion also promoted compensatory liver proliferative response secondary to decreased progression of liver injury. Overall, hepatocyte-specific EGFR deletion halted the progression of AILI. Our study established an unexpected death promoting function of EGFR in AILI progression, which has wide implications in liver biology.
2025-11-13 | GSE309117 | GEO
Project description:Epidermal growth factor receptor (EGFR) is mostly known for its proliferative role in liver. Our earlier investigations indicated a paradoxical cell-death promoting facet of EGFR in acetaminophen (APAP)-induced liver injury (AILI) model. The current study investigates this unexpected role of EGFR in promoting AILI using a hepatocyte-specific EGFR deletion mouse model. Hepatocyte-specific EGFR-deficient mice were generated by administering AAV8-TBG-CRE in EGFRfl/fl mice and were subsequently treated with a severely toxic dose (500 mg/kg) of APAP. Liver injury, regeneration and associated signaling pathways were assessed at different time intervals. EGFR deletion significantly attenuated the progression of liver injury (beyond 12hr post-APAP) without altering early liver injury (up to 6 hr) following APAP overdose. Consistently, the key injury initiating events such as APAP-protein adducts formation and early JNK activation remained intact in EGFR-deficient mice. However, EGFR deletion restricted prolonged JNK activation and its mitochondrial translocation, resulting in reduced propagation of mitochondrial damage and release of cell death drivers. Further, the replenishment of antioxidant glutathione (GSH), which is known to limit the progression of liver injury, was strikingly faster in EGFR-deficient mice. RNA-seq analysis and consequent validation revealed marked upregulation of autophagy and its transcriptional regulator TFEB, a key response to remove damaged mitochondria, in EGFR-deficient mice. Paradoxically, EGFR deletion also promoted compensatory liver proliferative response secondary to decreased progression of liver injury. Overall, hepatocyte-specific EGFR deletion halted the progression of AILI. Our study established an unexpected death promoting function of EGFR in AILI progression, which has wide implications in liver biology.
2025-11-13 | GSE309115 | GEO
Project description:To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Genetic suppression of EGFR* induction led to significant tumor regression and prolonged survival. But in spite of the initial response, the tumors relapsed invariably and propagated independent of EGFR*. We used microarrys to directly compare geen expression of control and relapse tumors and identified gene sets specifically activated in relapse tumors. Control and relasped glioma samples upon mutant EGFR extinction were selected for RNA extraction and hybridization on Affymetrix microarrays.
2015-01-08 | E-GEOD-64751 | biostudies-arrayexpress
Project description:Intratumoral heterogeneity in EGFR mutant NSCLC results in divergent resistance mechanisms in response to EGFR tyrosine kinase inhibition We used microarrays to investigate the gene expression underlying EGFR TKI resistance with a mesenchymal phenotype.
2016-06-04 | GSE69181 | GEO
Project description:Non-small cell lung cancers (NSCLCs) harboring activating EGFR mutants show dramatic responses to EGFR TKIs, such as erlotinib and geffitinib. However, nearly all patients show relapse within 1 year after initial treatment. We used microarrays to detail global gene expression changes in EGFR mutant cells vs. WT cells responding to erlotinib. 4 EGFR mutant and 4 WT NSCLC cells were treated with or without erlotinib for 24 hr, followed by RNA extraction and hybridization on Affymetrix microarrays.
2014-05-16 | E-GEOD-57156 | biostudies-arrayexpress
Project description:Introduction: Overcoming of acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable obstacle for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are very complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR mutated lung cancer largely unknown. Methods: Osimertinib and afatinib-resistant EGFR-mutated lung cancer cells were established using by a stepwise method. Microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant NSCLC cells. Results: Microarray analysis was evaluated by bioinformatics analysis through medical-industrial collaboration. CRNDE and DGCR5 lncRNAs were highly expressed in EGFR-TKIs-resistant cells. CRNDE binds to eIF4A3 protein, down-regulates eIF4A3 and MUC1 expression, and down-regulates p-EGFR expression. CRNDE inhibition activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity and restored sensitivity to EGFR-TKIs. Conclusions: We identified lncRNA CRNDE associated with resistance to EGFR-TKIs in EGFR-mutant NSCLC cells. CRNDE may be a novel therapeutic target for EGFR mutant NSCLC patients.
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