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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.

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

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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