Dataset Information

Single cell expression profiling of brain tumors in mice intracranially injected with 2x105 glioblastoma tumor cells isolated from NTv-a;hUBC-CreERT2;Adar1flox/flox mice and treated with tamoxifen to induce Adar1 deletion, or with vehicle control.

ABSTRACT: Glioblastomas are the most frequent and aggressive primary brain tumors. Current treatments invariably fail, a consequence of the pronounced heterogeneity and plasticity of glioblastoma cells, as well as the contribution of an immunosuppressive microenvironment that promotes tumor progression and resistance to therapy. Here, we exploited an innate immunity checkpoint, RNA sensing, to simultaneously target cancer cells and their supporting microenvironment. Using various immunocompetent mouse models of glioblastoma, we found that genetic deletion of Adar1, a key regulator of the RNA sensing pathway, resulted in significantly reduced tumor growth and prolonged survival. Mechanistically, these effects were mediated by two processes: cancer-cell intrinsic responses and reprogramming of the immune microenvironment that fostered a pro-inflammatory, anti-tumoral state via type I interferon signaling. These findings establish proof of concept for the therapeutic potential of targeting ADAR1 in glioblastoma, offering new strategies for the treatment of this aggressive disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE295661 | GEO | 2025/09/02

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Sensing of double-stranded RNA (dsRNA) is an important component of innate immunity. Proteins like PKR and MDA5 recognize dsRNA and activate various pathways to fight viral infection. In addition to viral dsRNA, many endogenous RNAs containing double-stranded regions can be misrecognized as immunogenic. The RNA editing enzyme ADAR1, specifically its p150 isoform, has been shown to suppress activation of PKR and MDA5 through its A-to-I editing activity. While the cytoplasmic ADAR1-p150 isoform has been well established within this role, the functions of the nuclear ADAR1-p110 isoform are less understood. To address this knowledge gap, we utilized proximity labeling by APEX2 to identify putative ADAR1-p110 interacting proteins. We identified 110 proteins across three breast cancer cell lines that either interact with p110 or are within close proximity. Many of these proteins have known roles in RNA metabolism. Nine of the identified proteins belong to the DEAD or DEAH box families of RNA helicases, including DHX9. DHX9 is overexpressed in breast cancer, with expression closely correlated with that of p110. By co-immunoprecipitation we confirmed that p110 interacts with DHX9. Knockdown of DHX9 in several triple-negative breast cancer cell lines caused cell death and activation of the dsRNA sensor PKR. In two cell lines that are refractory to knockdown of ADAR1, the combined knockdown of DHX9 and ADAR1 caused a substantial increase in PKR activity, where knockdown of either alone had no effect. Knockdown of DHX9 and ADAR1 caused activation of the type I IFN pathway, RNase L and NF-KB signaling. Activation of these proteins and pathways was not seen with individual knockdown of ADAR1 or DHX9. Activation of PKR following combined knockdown of ADAR1 and DHX9 could be rescued by expression of p110, p150, DHX9, and catalytically inactive DHX9. Additionally PKR activation could be rescued by the dsRBM of DHX9, revealing an important role for dsRBMs in suppressing PKR activation. Together these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways.

Dataset Information

Single cell expression profiling of brain tumors in mice intracranially injected with 2x105 glioblastoma tumor cells isolated from NTv-a;hUBC-CreERT2;Adar1flox/flox mice and treated with tamoxifen to induce Adar1 deletion, or with vehicle control.

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets