Dataset Information

Multi-omics Dissection of MAPK-driven Senescence Unveils Therapeutic Vulnerabilities in KIAA1549::BRAF-fusion Pediatric Low-Grade Glioma Models

ABSTRACT: This study investigates molecular mechanisms regulating oncogene-induced senescence (OIS) and senescence-associated secretory phenotype (SASP) in pediatric low-grade gliomas (pLGGs). Using multi-omics analysis of a pilocytic astrocytoma cell line, we identified key OIS effectors and pathways affected by MAPK inhibition. We constructed a network of MAPK-OIS-SASP interdependencies, revealing potential therapeutic targets. Several compounds targeting signaling nodes were identified and validated, suggesting new treatment strategies for pLGGs.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Brain Cancer

SUBMITTER: Anja Stefanski

LAB HEAD: Anja Stefanski

PROVIDER: PXD060126 | Pride | 2025-06-30

REPOSITORIES: Pride

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Publications

Multi-omics dissection of MAPK-driven senescence unveils therapeutic vulnerabilities in KIAA1549::BRAF-fusion pediatric low-grade glioma models.

Sigaud Romain R Stefanski Anja A Selt Florian F Kocher Daniela D Usta Diren D Picard Daniel D Büdenbender Isabel I Remke Marc M Pfister Stefan M SM Jones David T W DTW Brummer Tilman T Witt Olaf O Milde Till T

Signal transduction and targeted therapy 20250623 1

Pilocytic astrocytomas (PA), the most common pediatric low-grade gliomas (pLGGs), are characterized by genetic MAPK pathway alterations leading to constitutive activation and oncogene-induced senescence (OIS) accompanied with the senescence-associated secretory phenotype (SASP). This study investigates the molecular mechanisms of signaling pathways regulating OIS and SASP in pLGGs using a multi-omics approach. We utilized senescent DKFZ-BT66 cells derived from a primary KIAA1549::BRAF-fusion pos ...[more]

PMID: 40550805

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Project description:Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces Ã¢Â?Â?SASP-likeÃ¢Â?Â? inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression. This study examines the genome-wide distribution of gH2A.x and H3K4me3 by chIP-seq, using input and whole histone subunit H3 (respectively) as controls for local sonication efficiency bias. Each of the four chIPs has a single replicate each in (i) IMR90 fibroblasts transfected with a scramble control vector, (ii) the same cells subject to oncogene-induced senescence by stimulation of H-Ras V12, and (iii) in OIS cells with a shRNA targeting MLL1. Additionally, gH2A.x and input were sequenced with another replicate in control and OIS cells (both scramble control).

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