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ABSTRACT: METTL3 suppresses pancreatic ductal adenocarcinoma progression through activating endogenous dsRNA-induced anti-tumor immunity

PROVIDER: PRJNA946548 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23911046_1.fastq.gz	Fastqsanger.gz
	SRR23911046_2.fastq.gz	Fastqsanger.gz
	SRR23911047_1.fastq.gz	Fastqsanger.gz
	SRR23911047_2.fastq.gz	Fastqsanger.gz
	SRR23911048_1.fastq.gz	Fastqsanger.gz

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Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity [CRISPR screen]

Project description:Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyl-transferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti-PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti-PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the mole-cular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic.

2023-11-04 | GSE246837 | GEO

Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity [QuantSeq 3’ mRNA-Seq]

Project description:Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyltransferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti–PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti–PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the molecular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic.

2024-01-14 | GSE252960 | GEO

Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity [ONT direct RNA-seq]

Project description:Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyltransferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti–PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti–PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the molecular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic.

2024-01-06 | GSE252537 | GEO

Transcriptomic analysis of tumor infiltrating CD8+ T cells during PDAC progression

Project description:CD8+ T cells are master effectors of anti-tumor immunity and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumormicroenvironment can dampen their ability to control tumor progression. We will analyze the transcriptional profile of CD8+ T cells infiltrating murine tumors during progression in a pre-cinical model pancreatic ductal adenocarcinoma (PDA).

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mRNA expression data from RalGAPβ-deficient human pancreatic ductal adenocarcinoma cells (MIA PaCa-2), MIA PaCa-2 parental cells, and MIA PaCa-2 control cells

Project description:Pancreatic ductal adenocarcinoma, caused by activating mutation in K-Ras, is an aggressive malignancy due to its early invasion and matastasis. Ral GTPases, negatively regulated by RalGAP, are activated downstream of Ras and play a crucial role in development and progression of pancreatic ductal adenocarcinoma. However, the underlying mechanisms remain unclear. We used microarrays to detail the global programme of gene expression underlying the human pancreatic ductal adenocarcinoma cell line, MIA PaCa-2 with RalGAPβ deficiency or not, and identified distinct classes of Ral activation-related mRNA.

2023-04-24 | GSE223382 | GEO

Targeting novel m6A reader KHSRP impairs pancreatic ductal adenocarcinoma progression via attenuating FAK signaling

Project description:We report KH-type splicing regulatory protein (KHSRP) as a novel m6A reader with oncogenic functions in pancreatic ductal adenocarcinoma (PDAC). KHSRP recognizes and stabilizes its target mRNAs (e.g., MET, ITGAV and ITGB1) in an m6A-dependent manner, therefore activating downstream FAK signaling and promoting PDAC progression. Targeting KHSRP shows promising anti-tumoral effects in vitro and in vivo, indicating that KHSRP may serve as a therapeutic target for PDAC.

2024-07-30 | GSE229230 | GEO

Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity [RNA-seq]

Project description:Therapies that enhance anti-tumour immunity have dramatically changed the natural history of a range of cancers. Consequently, leveraging non-overlapping mechanisms to further increase the immunogenicity of cancer cells remains a major priority. Here, using a novel inhibitor of the RNA methyltransferase, METTL3, we demonstrate that enzymatic inhibition and a global decrease in N6-methyladenosine (m6A) results in double stranded RNA formation and a profound cell-intrinsic interferon response. By monitoring nascent mRNA, we show that the downstream induction of interferon stimulated genes (ISG) is coupled to a global increase in mRNA stability due to decreased m6A. One of the primary sequelae of this process is an increased expression and stability of genes associated with antigen presentation via MHC-I3. With unbiased global CRISPR screens we demonstrate that components of dsRNA sensing and interferon signalling are the primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. As PDL1, a key immune checkpoint, is also induced by interferon3, we show in a range of immunocompetent mouse models that whilst METTL3 inhibition alone is equally efficacious to anti-PD1 therapy, the combination has far greater pre-clinical activity. Importantly, using SPLINTR barcoding4, we demonstrate at single clone resolution that anti-PD1 and METTL3 inhibition target distinct malignant clones and the combination of these therapies augment anti-tumour immunity to overcome clones insensitive to the single agents. Together these data provide the molecular and pre-clinical rationale for employing METTL3 inhibitors to promote anti-tumour immunity in the clinical setting.

2023-10-12 | GSE217920 | GEO

PRMT1 suppresses anti-tumor immunity

Project description:PRMT1 suppresses anti-tumor immunity

| PRJNA840921 | ENA

RNA-SEQ analysis of pancreatic ductal adenocarcinoma tumours in Pdx1-Cre;lsl-KRas[G12D] (KC), Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM] (KMC), Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM];c-Myc[fl/+] (KMC-Mycfl/+), and Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM];Zbtb17[fl/fl] mice (KMC-Miz1fl/fl)

Project description:Activation of endogenously expressed KRas[G12D] in the pancreas of mice gives rise primarily to early stage PanIN lesions, however such lesions can occasionally progress to end-stage ductal adenocarcinoma (PDAC). Progression of KRas[G12D]- initiated lesions to PDAC is accelerated by modest expression of MYC from the Rosa26 locus. Deletion of 1 copy of endogenous c-Myc or both copies of endogenous Zbtb17 (aka Miz1), slows progression to PDAC and extends healthful survival of Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM] (KMC) mice. Tumours were removed from mice with all 4 genotypes and validated by histological examination prior to RNA-SEQ analysis.

2020-03-16 | E-MTAB-8797 | biostudies-arrayexpress

Multi-omics analysis of hematopoietic progenitors in the fetal liver of Mettl3 deficient mice

Project description:N6-methyladenosine (m6A) is the most abundant RNA modification, but little is known about its role in mammalian hematopoietic development. Conditional deletion of the m6A writer METTL3 in murine fetal liver results in hematopoietic failure and perinatal lethality. Loss of METTL3 and m6A activates an aberrant innate immune response, mediated by the formation of endogenous double-stranded RNAs (dsRNAs). The aberrantly formed dsRNAs are long, highly m6A modified in their native state, characterized by low folding energies and predominantly protein-coding. We identified coinciding activation of innate immune pattern recognition receptor pathways normally tasked with the detection of foreign dsRNAs. Our results suggest that m6A modification protects against endogenous dsRNA formation and a deleterious innate immune response during mammalian hematopoietic development. Keywords: innate immune response, dsRNA, RNA modification, N6-methyladenosine, METTL3, hematopoietic development, RNA-seq, H3K4me3, CUT&RUN, J2-RIP, dropseq, single cell RNA-seq, scRNA-seq, LSK, fetal liver

2020-06-01 | GSE148882 | GEO

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