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Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers [Spatial Transcriptomics by Resolve Biosciences Molecular Cartography]

ABSTRACT: Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers [Spatial Transcriptomics by Resolve Biosciences Molecular Cartography]

PROVIDER: PRJNA1128058 | ENA |

REPOSITORIES: ENA

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Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers [Spatial Transcriptomics by Resolve Biosciences Molecular Cartography]

Project description:First-line immune checkpoint inhibitor (ICI) combinations have shown responses in subsets of patients with advanced hepatocellular carcinoma (HCC). Nearly half of patients are Wnt active with mutations in CTNNB1 (encoding for beta-catenin), AXIN1/2, or APC, and demonstrate limited benefit to ICI due to an immunosuppressive tumor microenvironment. We investigated a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1) in multiple beta-catenin-mutated immunocompetent HCC mouse models, observing complete response. Integrated single-cell and spatial transcriptomics revealed complete cellular and zonal reprogramming of CTNNB1-mutated tumors, and a spatiotemporal shift in innate immune surveillance with intra-tumoral pro-inflammatory myeloid infiltration following LNP-CTNNB1 intervention. beta-catenin knockdown initiated tumor cell-intrinsic type I/II interferon signaling accompanied by IRF2 upregulation, which was suppressed in CTNNB1-mutated HCCs. IRF2 re-expression in beta-catenin-mutated HCC restored adaptive tumor immunity with increased CD4+ T cells and impaired recruitment of resident T regulatory cells. Finally, LNP-CTNNB1 synergized with ICI in advanced-stage disease through increasing intra-tumoral recruitment of cytotoxic T cells. In summary, RNAi-mediated inhibition of CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through remodeling both tumor cell intrinsic signaling and global immune surveillance, thus providing rationale for clinical investigations.

2025-05-02 | GSE270708 | GEO

Spatial transcriptomic data of P5 mouse cortical somatostatin neurons

Project description:Probe panel for 94 genes designed using Resolve Biosciences proprietary design software, as reported in table S4 of the manuscript . Molecular Cartography (100-plex combinatorial single molecule fluorescence in-situ hybridization)

2024-02-09 | GSE247005 | GEO

Resolve smFISH spatial transcriptomics on the GL261 tumor bearing hemisphere, treated with PBS / aPD1 / CSI / CSI+aPD1

Project description:We performed Resolve Molecular Cartography to assess the effect of CpG-STAT3ASO+anti-PD1 therapy on immune cells from GL261 high grade glioma model.

2025-05-19 | GSE292668 | GEO

Dynamic control of metabolic zonation and liver repair by endothelial cell Wnt2 and Wnt9b revealed by single cell spatial transcriptomics using Molecular Cartography

Project description:The conclusive identity of Wnt proteins regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of beta-catenin. Using single-cell analysis of liver cells from various species, a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3 shown to be the major Wnt cell source, was identified. Conditional EC-elimination of Wnt2 and Wnt9b led to perturbation of LZ with not only loss of beta-catenin targets in zone 3, but also re-appearance of zone 1 genes in zone 3, unraveling dynamicity as revealed by single-cell spatial transcriptomics using Molecular Cartography. Defective LR observed in the knockouts phenocopied other models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts. Molecular Cartography on the livers of the agonist-treated animal revealed changes in LZ. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF.

2022-09-01 | GSE199463 | GEO

Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers

Project description:Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers

| PRJNA1129135 | ENA

Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers [Bulk RNA-seq CTNNB1/NFE2L2]

Project description:Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers [Bulk RNA-seq CTNNB1/NFE2L2]

| PRJNA1228038 | ENA

Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers [Spatial Transcriptomics by 10X Visium]

Project description:Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers [Spatial Transcriptomics by 10X Visium]

| PRJNA1129143 | ENA

Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers [Single-cell RNA-seq GEX]

Project description:Precision targeting of beta-catenin induces tumor reprogramming and immunity in hepatocellular cancers [Single-cell RNA-seq GEX]

| PRJNA1128068 | ENA

Global transcript structure resolution of high gene density genomes through multi-platform data integration: deepCAGE

Project description:deepCAGE was used in conjunction with Pacific Biosciences Iso-Seq and Illumina RNA-Seq to globally resolve transcript structures in replicating Epstein-Barr virus.

2016-07-08 | GSE79293 | GEO

Genome-wide transcript structure resolution in murine gammaherpesvirus 68: Iso-Seq

Project description:Pacific Biosciences Iso-Seq was used in conjunction with Illumina RNA-Seq and deepCAGE to globally resolve transcript structures in lytic murine gammaherpesvirus 68.

2019-06-25 | GSE117650 | GEO

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