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Loss of ATM accelerates pancreatic cancer formation and epithelial–mesenchymal transition

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is associated with accumulation of particular oncogenic mutations and recent genetic sequencing studies have identified ataxia telangiectasia-mutated (ATM) mutations in PDAC cohorts. Here we report that conditional deletion of ATM in a mouse model of PDAC induces a greater number of proliferative precursor lesions coupled with a pronounced fibrotic reaction. ATM-targeted mice display altered TGFβ-superfamily signalling and enhanced epithelial-to-mesenchymal transition (EMT) coupled with shortened survival. Notably, our mouse model recapitulates many features of more aggressive human PDAC subtypes. Particularly, we report that low expression of ATM predicts EMT, a gene signature specific for Bmp4 signalling and poor prognosis in human PDAC. Our data suggest an intimate link between ATM expression and pancreatic cancer progression in mice and men.

ORGANISM(S): Mus musculus

PROVIDER: GSE68808 | GEO | 2015/08/07

SECONDARY ACCESSION(S): PRJNA283830

REPOSITORIES: GEO

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Loss of ATM accelerates pancreatic cancer formation and epithelial–mesenchymal transition

Project description:Pancreatic ductal adenocarcinoma (PDAC) is associated with accumulation of particular oncogenic mutations and recent genetic sequencing studies have identified ataxia telangiectasia-mutated (ATM) mutations in PDAC cohorts. Here we report that conditional deletion of ATM in a mouse model of PDAC induces a greater number of proliferative precursor lesions coupled with a pronounced fibrotic reaction. ATM-targeted mice display altered TGFβ-superfamily signalling and enhanced epithelial-to-mesenchymal transition (EMT) coupled with shortened survival. Notably, our mouse model recapitulates many features of more aggressive human PDAC subtypes. Particularly, we report that low expression of ATM predicts EMT, a gene signature specific for Bmp4 signalling and poor prognosis in human PDAC. Our data suggest an intimate link between ATM expression and pancreatic cancer progression in mice and men. KC (Atm+/+) and AKC (Atm-/-) mouse pancreata at 5 weeks old (n= 3 KC; n= 3 AKC) or 10 weeks old (n=3 KC; n=4 AKC) were subjected to microarray analysis.

2015-08-07 | E-GEOD-68808 | biostudies-arrayexpress

Transcription profiling of ATM +/+, ATM +/- and ATM -/- human lymphoblastoid cell lines exposed to 5 Gy IR at 0, 4 and 24 hours to identify expression phenotypes in Ataxia Telangiectasia carriers and patients

Project description:Transcription profiling of ATM (Ataxia Telangiectasia Mutated) +/+ (Control), ATM +/- (AT Carrier) and ATM -/- (AT patient) human lymphoblastoid cell lines exposed to 5 Gy IR at 0, 4 and 24 hours to identify expression phenotypes in Ataxia Telangiectasia carriers and patients

2008-07-29 | E-TABM-321 | biostudies-arrayexpress

Reduced phosphorylated ATM expression is associated with poor prognosis and gemcitabine resistance in pancreatic cancer

Project description:Background & Aims: Loss of ataxia-telangiectasia mutated, occurring in patients with multiple primary malignancies, including pancreatic cancer, is associated with poor prognosis. This study investigated the detailed molecular mechanism through which ataxia-telangiectasia mutated expression affects the prognosis of pancreatic-cancer patients Methods: Ataxia-telangiectasia mutated and phosphorylated ataxia-telangiectasia mutated levels in pancreatic-cancer patients who underwent surgical resection were analyzed using immunohistochemistry staining. RNA sequencing was performed on ataxia-telangiectasia mutated-knockdown pancreatic-cancer cells to elucidate the mechanism underlying the involvement of ataxia-telangiectasia mutated in pancreatic cancer. Results: Immunohistochemical analysis showed that 15.3% and 27.8% of clinical samples had low levels of ataxia-telangiectasia mutated and phosphorylated ataxia-telangiectasia mutated, respectively. Low phosphorylated ataxia-telangiectasia mutated expression substantially reduced overall and disease-free survival in pancreatic-cancer patients. Loss of ataxia-telangiectasia mutated promoted MET and NTN1 over-expression via hypoxia-inducible factor-1α, thereby enhancing pancreatic-cancer cell proliferation and migration. Conclusions: These results demonstrate that the loss of ataxia-telangiectasia mutated activates downstream proto-oncogenes, inhibits apoptosis, and promotes tumor growth; moreover, loss of phosphorylated ataxia-telangiectasia mutated leads to poor prognosis in pancreatic-cancer patients. Thus, ataxia-telangiectasia mutated may serve as a potential molecular marker to monitor patient prognosis and as a potential target for pancreatic cancer therapy

2023-02-13 | GSE224882 | GEO

Antithetical NFATc1-Sox2 and p53-miR-200 signalling networks governs pancreatic cancer cell plasticity and tumour progression

Project description:Pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial mesenchymal transdifferentiation (EMT) in adaption to environmental cues, including inflammation, a process that combines tumour cell dedifferentiation with dissemination and acquisition of stemness features. However, the mechanisms coupling inflammation-induced signalling pathways with EMT and stemness remain largely unknown. Here, we reveal the inflammation-induced transcription factor NFATc1 as a central regulator of pancreatic cancer cell plasticity.

2015-02-10 | E-MTAB-2324 | biostudies-arrayexpress

ROS-activated ATM-dependent phospho-signaling

Project description:ATM (ataxia-telangiectasia mutated) protein plays a central role in phosphorylating a network of proteins in response to DNA double strand breaks. These phosphorylated proteins function in signalling pathways designed to maintain the stability of the genome and minimize the risk of disease by controlling cell cycle checkpoints, initiating DNA repair and regulating gene expression. We employed a modified TiSH global quantitative phosphoproteomics approach to identify cytoplasmic proteins altered in their phosphorylation state in control and A-T cells in response to oxidative damage. We demonstrated that ATM was activated by oxidative damage in the cytoplasm as well as in the nucleus and identified a total of 9,612 phosphorylation sites including 6,650 high confidence sites mapping to 2,536 unique proteins.

2016-01-04 | PXD002850 | Pride

ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation [B16 vivo]

Project description:Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia Telangiectasia Mutated (ATM) protein plays a central role in sensing DNA double strand breaks and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance immune checkpoint blockade (ICB) therapy. However, the molecular mechanism involved is not clearly elucidated. Here we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA and activation of the cGAS/STING pathway. Genetic depletion of ATM in murine cancer cells significantly delayed tumor growth in syngeneic mouse hosts in a T-cell dependent manner. Furthermore, chemical inhibition of ATM significantly potentiated anti-PD1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating TFAM, which led to mitochondrial DNA leakage into the cytoplasm. Moreover, our analysis of data from a large patient cohort indicated that ATM mutations, especially nonsense mutations, predicted for clinical benefits for ICB therapy. Our study therefore provides strong evidence that ATM may serve both as a therapeutic target and a biomarker to enable ICB therapy.

2023-11-18 | GSE161922 | GEO

ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation [4T1 in vitro]

2023-11-18 | GSE161912 | GEO

ATM regulates a DNA damage response post-transcriptional RNA operon in lymphocytes

Project description:Maintenance of genomic stability depends on the DNA damage response (DDR), a biological barrier in early stages of cancer development. Failure of this response results in genomic instability and high predisposition toward lymphoma, as seen in patients with ataxia-telangiectasia mutated (ATM) dysfunction. ATM activates multiple cell cycle checkpoints and DNA repair following DNA damage, but its influence on posttranscriptional gene expression has not been examined on a global level. We show that ionizing radiation (IR) modulates the dynamic association of the RNA-binding protein HuR with target mRNAs in an ATM-dependent manner, potentially coordinating the genotoxic response as an RNA operon. Pharmacologic ATM inhibition and use of ATM-null cells revealed a critical role for ATM in this process. Numerous mRNAs encoding cancer-related proteins were differentially associated with HuR depending on the functional state of ATM, in turn affecting expression of encoded proteins. The findings presented here reveal a previously unidentified role of ATM in controlling gene expression post-transcriptionally. Dysregulation of this DDR RNA operon is likely relevant to lymphoma development in ataxia-telangiectasia individuals. These novel RNA regulatory modules and genetic networks provide critical insight into the function of ATM in oncogenesis.

2011-01-05 | GSE25848 | GEO

Inhibition of the ATM kinase rescues planarian regeneration after lethal radiation

Project description:As stem cells divide, they acquire mutations that can be passed on to daughter cells. To mitigate potentially deleterious outcomes, cells activate the DNA damage response (DDR) network, which governs several potential cellular outcomes following DNA damage, including repairing DNA or undergoing apoptosis. At the helm of the DDR are three PI3-like kinases including Ataxia Telangiectasia Mutated (ATM). We report here that knockdown of ATM in planarian flatworms enables stem cells to withstand lethal doses of radiation which would otherwise induce cell death. In this context, stem cells circumvent apoptosis, replicate their DNA, and recover function using homologous recombination-mediated DNA repair. Despite radiation exposure, atm knockdown animals survive long-term and regenerate new tissues. These effects occur independently of ATM’s canonical downstream effector p53. Together, our results demonstrate that in planarians, ATM regulates radiation-induced apoptosis. This acute, ATM-dependent apoptosis is a key determinant of long-term animal survival. Our results suggest that inhibition of ATM in these organisms could therefore potentially favor cell survival after radiation without obvious effects on stem cell behavior.

2022-12-25 | GSE190454 | GEO

ATM regulates a DNA damage response post-transcriptional RNA operon in lymphocytes

2011-01-05 | E-GEOD-25848 | biostudies-arrayexpress

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