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

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE181379 | GEO | 2022/01/10

REPOSITORIES: GEO

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

Project description:Despite the progress in medicine, no significant advancement in the standard of care for glioblastoma (GBM) patients have been reached. GBM heterogeneity, poor blood–brain barrier penetration and resistance to therapy highlight the need for new targets and clinical treatments. A step toward clinical translation includes the eradication of GBM Tumor-Initiating Cells (TICs), responsible for GBM heterogeneity and relapse. By using patient-derived TICs and xenograft orthotopic models, we demonstrate that Lysine-specific histone demethylase 1A (LSD1) is a druggable target in GBM. Here, we analyze the effect of LSD1i treatment on histone H3K4 in primary human cells and mouse brains.

2022-04-14 | PXD025781 | Pride

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

Project description:Tumor-initiating cells (TICs) play a critical role in glioblastoma (GBM) maintenance being responsible for its heterogeneity and resistance to standard therapy. A step toward clinical translation includes GBM TIC targeting. Among the molecules tested for GBM treatment, are those targeting epigenetic modifiers. By using patient-derived TICs and xenograft orthotopic models, we identified Lysine-specific histone demethylase 1A (LSD1) as a potentially druggable target in GBM. LSD1-directed therapy by means of the selective, orally bioavailable and brain penetrant inhibitor DDP_38003 effectively impairs growth, stem-like features and tumorigenic potential of GBM TICs. Our findings point to LSD1 as a positive regulator of Activating Transcription Factor 4 (ATF4)-dependent response in all stress conditions arising during tumor growth and therapy. Thus, through the downregulation of either ATF4 and its adaptive genes, LSD1 targeting is likely a promising strategy to hit GBM TICs by counteracting the ATF4-mediated adaptation to stress.

2022-01-10 | GSE181378 | GEO

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

2022-01-10 | GSE181372 | GEO

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

2022-01-10 | GSE181366 | GEO

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

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

| PRJNA751881 | ENA

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

Project description:LSD1-directed therapy affects glioblastoma tumorigenicity by deregulating the protective ATF4-dependent integrated stress response [ChIP-seq]

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

Project description:LSD1-directed therapy affects glioblastoma tumorigenicity by deregulating the protective ATF4-dependent integrated stress response [RNA-seq]

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

Project description:LSD1-directed therapy affects glioblastoma tumorigenicity by deregulating the protective ATF4-dependent integrated stress response [ATAC-seq]

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Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression.

Project description:The available evidence suggests that the lethality of glioblastoma is driven by small subpopulations of cells that self-renew and exhibit tumorigenicity. It remains unclear whether tumorigenicity exists as a static property of a few cells or as a dynamically acquired property. We used tumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolated from established and primary glioblastoma lines. Our results indicate that glioblastoma tumorigenicity is largely deterministic, yet the property can be acquired spontaneously at low frequencies. Further, these dynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1 (LSD1). LSD depletion increases trimethylation of histone 3 lysine 4 at the avian myelocytomatosis viral oncogene homolog (MYC) locus, which elevates MYC expression. MYC, in turn, regulates oligodendrocyte lineage transcription factor 2 (OLIG2), SRY (sex determining region Y)-box 2 (SOX2), and POU class 3 homeobox 2 (POU3F2), a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Our model suggests epigenetic regulation of key transcription factors governs transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development.

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Chromosomal Instability Affects the Tumorigenicity of Glioblastoma Tumor-Initiating Cells.

Project description:UnlabelledTumors are dynamic organs that evolve during disease progression with genetic, epigenetic, and environmental differences among tumor cells serving as the foundation for selection and evolution in tumors. Tumor-initiating cells (TIC) that are responsible for tumorigenesis are a source of functional cellular heterogeneity, whereas chromosomal instability (CIN) is a source of karyotypic genetic diversity. However, the extent that CIN contributes to TIC genetic diversity and its relationship to TIC function remains unclear. Here, we demonstrate that glioblastoma TICs display CIN with lagging chromosomes at anaphase and extensive nonclonal chromosome copy-number variations. Elevating the basal chromosome missegregation rate in TICs decreases both proliferation and the stem-like phenotype of TICs in vitro Consequently, tumor formation is abolished in an orthotopic mouse model. These results demonstrate that TICs generate genetic heterogeneity within tumors, but that TIC function is impaired if the rate of genetic change is elevated above a tolerable threshold.SignificanceGenetic heterogeneity among TICs may produce advantageous karyotypes that lead to therapy resistance and relapse; however, we found that TICs have an upper tolerable limit for CIN. Thus, increasing the chromosome missegregation rate offers a new therapeutic strategy to eliminate TICs from tumors. Cancer Discov; 6(5); 532-45. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.

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