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KRAS and MEK activation promote antisense oligonucleotide uptake and activity by limiting collagen production

ABSTRACT: KRAS and MEK activation promote antisense oligonucleotide uptake and activity by limiting collagen production

PROVIDER: PRJNA723544 | ENA |

REPOSITORIES: ENA

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KRAS and MEK activation promote antisense oligonucleotide uptake and activity by limiting collagen production

Project description:Using RNAseq we describe transcriptional changes downstream of MEK1 affecting RNA kncokdown following free uptake RNaseH1 gapmer antisense oligonucleotides

2021-04-22 | GSE172485 | GEO

GOLGA8 increases bulk antisense oligonucleotide uptake and activity in mammalian cells

Project description:GOLGA8 increases bulk antisense oligonucleotide uptake and activity in mammalian cells

| PRJNA830477 | ENA

GOLGA8 increases bulk antisense oligonucleotide uptake and activity in mammalian cells

Project description:Antisense oligonucleotides (ASOs) are short synthetic nucleic acids that recognize and bind to complementary RNA to modulate gene expression. It is well-established that single-stranded, phosphorothioate modified ASOs enter cells independent of carrier molecules, primarily via endocytic pathways, but that only a small portion of internalized ASO is released into the cytosol and/or nucleus rendering the majority of ASO as inaccessible to the targeted RNA. Identifying pathways that can increase the available ASO pool is valuable as a research tool and therapeutically. Here, we conducted a functional genomic screen for ASO activity by engineering GFP splice reporter cells and applying genome wide CRISPR gene activation. The screen can identify factors that enhance ASO splice modulation activity. Characterization of hit genes uncovered GOLGA8, a largely uncharacterized protein, as a novel positive regulator enhancing ASO activity by ~2-fold. Bulk ASO uptake is 5-fold higher in GOLGA8 overexpressing cells where GOLGA8 and ASOs are observed in the same intracellular compartments. We find GOLGA8 is highly localized to the trans-Golgi and readily detectable at the plasma membrane. Interestingly, overexpression of GOLGA8 increased activity for both splice modulation and RNase H1-dependent ASOs. Taken together, these results support a novel role for GOLGA8 in productive ASO uptake.

2022-04-26 | GSE201237 | GEO

Antisense oligonucleotide activity in tumour cells is influenced by intracellular LBPA distribution and 6 extracellular vesicles recycling

Project description:Next generation modified antisense oligonucleotides (ASOs) are commercially approved new therapeutic modalities, yet poor productive uptake and endosomal entrapment in tumour cells limit their broad application. We compared intracellular traffic of anti KRAS antisense oligonucleotide (AZD4785) in good and poor productive uptake tumour cells, PC9 and LK2 respectively. We found that the majority of AZD4785 is rapidly delivered to CD63+ late endosomes (LE) in both cell lines. Importantly, lysobisphosphatidic acid (LBPA) that triggers ASO LE escape is presented in CD63+ LE in PC9 but not in LK2 cells. Moreover, both cells recycle AZD4785 in the extracellular vesicles (EVs) however AZD4785 quantification by advanced mass spectrometry and proteomic analysis revealed that LK2 recycles more AZD4785 and RNA-binding proteins. Finally, stimulating LBPA intracellular production or blocking EV recycling enhanced AZD4785 activity in LK2 but not in PC9 cells thus offering novel strategy to possibly enhance ASO potency in poor productive uptake tumour cells.

2021-11-10 | PXD027804 | Pride

Tumor-associated macrophages derived from circulating inflammatory monocytes degrade collagen through cellular uptake

Project description:Tumor-associated macrophages derived from circulating inflammatory monocytes degrade collagen through cellular uptake

| PRJNA418920 | ENA

Tumor-associated macrophages derived from circulating inflammatory monocytes degrade collagen through cellular uptake

Project description:Physiologic turnover of interstitial collagen is mediated by a sequential pathway, in which collagen is fragmented by pericellular collagenases, endocytosed by specific collagen receptors, and routed to lysosomes for degradation by lysosomal cathepsins. Here, we used intravital microscopy to investigate if malignant tumors, which are characterized by high rates of extracellular matrix turnover, utilize a similar collagen degradation pathway. Tumors of epithelial, mesenchymal, or neural crest origin all displayed vigorous endocytic collagen degradation with an abundance of cells engaged in this process. These cells were identified as tumor-associated macrophage (TAM)-like cells that degraded collagen in a mannose receptor-dependent manner. Accordingly, increased intra-tumoral collagen was observed in mannose receptor-deficient mice. Whole transcriptome profiling uncovered a distinct extracellular matrix-catabolic signature of these collagen-degrading TAMs. Lineage-ablation studies revealed that collagen-degrading TAMs originated from circulating CCR2+ monocytes. The study identifies a novel function of TAMs in altering the tumor microenvironment through endocytic collagen turnover and establishes macrophages as centrally engaged in tumor-associated collagen degradation.

2018-01-01 | GSE107053 | GEO

Liver proteome upon in vivo N-acetylgalactosamine-conjugated antisense oligonucleotide silencing of ceramide synthase 2

Project description:Mouse liver proteome was investigated upon in vivo mouse treatment with a N-acetylgalactosamine-conjugated antisense oligonucleotide engineered to silence ceramide synthase 2 specifically in hepatocytes in vivo. The data is a part of a study on the involvement of ceramide enzymatic machinery in cardiovasular disorders and its potential as a target for the disease treatment.

2023-05-10 | PXD025957 | Pride

Oligonucleotide-based arrayCGH

Project description:Oligonucleotide-based arrayCGH

| PRJNA92921 | ENA

Expression data from dosing an antisense oligonucleotide in mice I

Project description:We used microarrays to globally profile the gene expression changes observed in liver after 3 days when dosing an antisense oligonucleotide in mice

2018-04-30 | GSE100697 | GEO

Expression data from transfection of an antisense oligonucleotide in 518A2 cells

Project description:We used microarrays to globally profile the gene expression changes observed after 3 days when transfecting an antisense oligonucleotide in 518A2 cells

2017-04-21 | GSE93185 | GEO

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