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ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275637 | GEO | 2024/08/31

REPOSITORIES: GEO

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ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma [PDX RNA-seq]

Project description:Chordoma, a rare and challenging primary bone malignancy, currently lacks effective targeted therapies. Despite surgical resection and adjuvant radiotherapy, prognosis remains poor. Recent preclinical studies have highlighted potential therapeutic targets, including the transcription factor TBXT, although clinical outcomes have been modest. In this study, we investigated the therapeutic potential of tRNA synthetase inhibitors, specifically halofuginone and halofuginol, in chordoma treatment. We conducted extensive drug screening, identifying these compounds as effective in reducing cell viability in chordoma cell lines through an ATF4-mediated stress response rather than TBXT regulation. Our findings were validated using RNA sequencing, which revealed significant upregulation of ATF4 and associated stress response genes. Additionally, halofuginone demonstrated significant tumour growth inhibition in an in vivo patient-derived xenograft model. These results suggest that targeting metabolic stress pathways via ATF4 activation presents a novel therapeutic approach for chordoma, warranting further clinical investigation.

2024-08-31 | GSE275636 | GEO

ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma [MUG-Chor RNA-seq]

2024-08-31 | GSE275458 | GEO

ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma

Project description:ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma

| PRJNA1152348 | ENA

ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma [PDX RNA-seq]

Project description:ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma [PDX RNA-seq]

| PRJNA1152352 | ENA

ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma [MUG-Chor RNA-seq]

Project description:ATF4-Mediated Metabolic Stress Response as a Therapeutic Vulnerability in Chordoma [MUG-Chor RNA-seq]

| PRJNA1150969 | ENA

Tumor suppressor BTG1 promotes PRMT1-mediated ATF4 function in response to cellular stress.

Project description:Cancer cells are frequently exposed to physiological stress conditions such as hypoxia and nutrient limitation. Escape from stress-induced apoptosis is one of the mechanisms used by malignant cells to survive unfavorable conditions. B-cell Translocation Gene 1 (BTG1) is a tumor suppressor that is frequently deleted in acute lymphoblastic leukemia and recurrently mutated in diffuse large B cell lymphoma. Moreover, low BTG1 expression levels have been linked to poor outcome in several solid tumors. How loss of BTG1 function contributes to tumor progression is not well understood. Here, using Btg1 knockout mice, we demonstrate that loss of Btg1 provides a survival advantage to primary mouse embryonic fibroblasts (MEFs) under stress conditions. This pro-survival effect involves regulation of Activating Transcription Factor 4 (ATF4), a key mediator of cellular stress responses. We show that BTG1 interacts with ATF4 and positively modulates its activity by recruiting the protein arginine methyl transferase PRMT1 to methylate ATF4 on arginine residue 239. We further extend these findings to B-cell progenitors, by showing that loss of Btg1 expression enhances stress adaptation of mouse bone marrow-derived B cell progenitors. In conclusion, we have identified the BTG1/PRMT1 complex as a new modifier of ATF4 mediated stress responses.

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LSD1-directed therapy affects glioblastoma tumorigenicity by deregulating the protective ATF4-dependent integrated stress response

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-01-10 | GSE181379 | GEO

ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma.

Project description:Tumors undergo nutrient stress and need to reprogram their metabolism to survive. The stroma may play a critical role in this process by providing nutrients to support the epithelial compartment of the tumor. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation by the direct control of ATF4 stability through its p62-mediated polyubiquitination. ATF4 upregulation by p62 deficiency in the stroma activates glucose carbon flux through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine generation as a source of nitrogen for stroma and tumor epithelial proliferation. Thus, p62 directly targets nuclear transcription factors to control metabolic reprogramming in the microenvironment and repress tumorigenesis, and identifies ATF4 as a synthetic vulnerability in p62-deficient tumor stroma.

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Ankyrin-3 as a Molecular Marker of Early Life Stress and Vulnerability to Psychiatric Disorders

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-07-06 | E-GEOD-84028 | biostudies-arrayexpress

Determining the mechanism of ATF4-mediated myofiber atrophy

Project description:This SuperSeries is composed of the SubSeries listed below.

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