Extracellular matrix remodeling regulates glucose metabolism through TXNIP destabilization
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA414447 | ENA |
REPOSITORIES: ENA
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Project description:The metabolic state of a cell is influenced by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM glycosaminoglycan hyaluronan and metabolism, treatment of both cells and xenograft tumors with hyaluronidase (HAase) triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinase-mediated induction of mRNA decay factor ZFP36, which targets TXNIP transcripts for degradation. Since TXNIP promotes internalization of the glucose transporter GLUT1, its acute decline enriches GLUT1 at the plasma membrane. Functionally, induction of glycolysis by HAase is required for concomitant acceleration of cell migration. This interconnection between ECM remodeling and metabolism is exhibited in dynamic tissues states including tumorigenesis and embryogenesis.
2018-05-12 | GSE105034 | GEO
Project description:The metabolic state of a cell is influenced by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as being among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM component hyaluronan and metabolism, treatment of cells and xenografts with hyaluronidase triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinase-mediated induction of the mRNA decay factor ZFP36, which targets TXNIP transcripts for degradation. Because TXNIP promotes internalization of the glucose transporter GLUT1, its acute decline enriches GLUT1 at the plasma membrane. Functionally, induction of glycolysis by hyaluronidase is required for concomitant acceleration of cell migration. This interconnection between ECM remodeling and metabolism is exhibited in dynamic tissue states, including tumorigenesis and embryogenesis.
| S-EPMC6151140 | biostudies-literature
Project description:Imatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but the primary and acquired imatinib resistance remains the big hurdle. Molecular mechanisms for CML resistance to tyrosine kinase inhibitors, beyond point mutations in BCR-ABL kinase domain, still need to be addressed. Here, we demonstrated that TXNIP is a novel BCR-ABL target gene. Suppression of TXNIP is responsible for BCR-ABL triggered glucose metabolic reprogramming and mitochondrial homeostasis. Mechanistically, Miz-1/P300 complex transactivates TXNIP through the recognition of TXNIP core promoter region, responding to the c-Myc suppression by either imatinib or BCR-ABL knockdown. TXNIP restoration sensitizes CML cells to imatinib treatment and compromises imatinib resistant CML cell survival, predominantly through the blockage of both glycolysis and glucose oxidation which results in the mitochondrial dysfunction and ATP production. In particular, TXNIP suppresses expressions of the key glycolytic enzyme, HK2 and LDHA, potentially through Fbw7-dependent c-Myc degradation. In accordance, BCR-ABL suppression of TXNIP provides a novel survival pathway for the transformation of mouse BM cells. Combination of drug inducing TXNIP expression with imatinib synergistically kills CML cells from patients and further extends the survival of CML mice. Thus, the activation of TXNIP represents an effective strategy for CML treatment to overcome resistance.
2023-05-03 | GSE218451 | GEO
Project description:The underlying pathomechanisms in diabetic retinopathy (DR) remains incompletely understood. The aim of this study was to add to the current knowledge about the particular role of retina Müller glial cells (RMG) in the initial processes of DR. Applying a mass spectrometric workflow, we investigated proteome changes of primary porcine RMG under short term diabetic cell culture treatment. We revealed global changes in RMG proteome indicated by a fundamental remodeling of ECM and focal adhesion processes which potentially leads to destabilization of the retinal inner limiting membrane. This is in line with our previous findings of a disrupted ILM in the retinae of a diabetic pig model and suggests an involvement of RMG in this process. Additionally, employing porcine organotypic retinal explant cultures, we demonstrate a specific decrease of RMG-associated SPP1 expression as a result of osmotic challenge induced by high glucose levels. We assume a loss of neuroprotective potential administrated by RMG and subsequent acceleration of neurodegenerative processes in DR.
2021-04-06 | PXD015879 | Pride
Project description:To identify genes implicated in metastatic colonization of the liver in colorectal cancer, we collected pairs of primary tumors and hepatic metastases before chemotherapy in 13 patients. We compared mRNA expression in the pairs of patients to identify genes deregulated during metastatic evolution. We then validated the identified genes using data obtained by different groups. The 33-gene signature was able to classify 87% of hepatic metastases, 98% of primary tumors, 97% of normal colon mucosa, and 95% of normal liver tissues in six datasets obtained using five different microarray platforms. The identified genes are specific to colon cancer and hepatic metastases since other metastatic locations and hepatic metastases originating from breast cancer were not classified by the signature. Gene Ontology term analysis showed that 50% of the genes are implicated in extracellular matrix remodeling, and more precisely in cell adhesion, extracellular matrix organization and angiogenesis. Because of the high efficiency of the signature to classify colon hepatic metastases, the identified genes represent promising targets to develop new therapies that will specifically affect hepatic metastasis microenvironment. 57 samples of patients with stage IV colorectal cancer. We compared using Affymetrix chips gene expression profiles between primary tumors and hepatic metastases
2013-09-01 | E-GEOD-49355 | biostudies-arrayexpress
Project description:Acidosis is a hallmark of the tumor microenvironment caused by the metabolic switch from glucose oxidative phosphorylation to glycolysis. It has been largely associated with tumor growth and progression, nevertheless, how acidosis promotes metastatic dissemination remains largely unknown. In this study, we established a long-term acidosis model using patient-derived lung cancer cells. By comparing xenograft inoculates at the cluster sizes of lung cancer circulating tumor cells, the acidosis cells display significantly higher incidence of secondary tumor establishment than their neutral pH counterparts. Transcriptomics analyses reveal a profound remodeling of the extracellular matrix in the acidosis cells, featuring the upregulation of ITGA4 and HAS3 genes, In clinical specimen, overexpression of both ITGA4 and HAS3 proteins are associated with primary tumors with metastatic ability, and their distribution is markedly accentuated around vascular mimicry structures in secondary tumors. We show that acidosis cells display higher ability of vascular mimicry in vitro, and are enriched in ABC transporter-dependent side population cells. Our data support that acidosis drives tumor metastatic colonization via enhanced extracellular matrix remodeling and vascular mimicry. Assessment on the prognostic value of tumor acidosis for metastasis and possible treatment directions are discussed.
2023-05-21 | GSE200546 | GEO
Project description:Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognised to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodelling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.
2024-08-12 | PXD051666 | Pride
Project description:To identify genes implicated in metastatic colonization of the liver in colorectal cancer, we collected pairs of primary tumors and hepatic metastases before chemotherapy in 13 patients. We compared mRNA expression in the pairs of patients to identify genes deregulated during metastatic evolution. We then validated the identified genes using data obtained by different groups. The 33-gene signature was able to classify 87% of hepatic metastases, 98% of primary tumors, 97% of normal colon mucosa, and 95% of normal liver tissues in six datasets obtained using five different microarray platforms. The identified genes are specific to colon cancer and hepatic metastases since other metastatic locations and hepatic metastases originating from breast cancer were not classified by the signature. Gene Ontology term analysis showed that 50% of the genes are implicated in extracellular matrix remodeling, and more precisely in cell adhesion, extracellular matrix organization and angiogenesis. Because of the high efficiency of the signature to classify colon hepatic metastases, the identified genes represent promising targets to develop new therapies that will specifically affect hepatic metastasis microenvironment. 57 samples of patients with stage IV colorectal cancer. We compared using Affymetrix chips gene expression profiles between primary tumors and hepatic metastases
2014-10-15 | E-GEOD-62321 | biostudies-arrayexpress
Project description:To examine the generality of our finding where the gene expression profile of TXNIP knockout in MDA-MB-231 cells resembles of that Myc overexpression transcriptional program, our lab has generated TXNIP null HCC70 (HCC70:TKO) and MB135 (MB135:TKO) cells. We characterized the gene exrpession programs of these cells by RNA-seq.
2023-02-07 | GSE222693 | GEO