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

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. Mutations in the serine/threonine kinase ataxia teleangiectasia mutated (ATM) have been linked to pancreatic ductal adenocarcinoma (PDAC) cohorts. Here Russellet al. show that loss of ATM induces a greater number of proliferative precursor lesions in a mouse model, recapitulating many features of human PDAC subtypes.

• Publication year

  2015

• Venue

  Nature Communications

• Publication date

  2015-07-29

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/ncomms8677PMID 26220524PMCID 4532798
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Pathologic Evaluation and Reporting of Intraductal Papillary Mucinous Neoplasms of the Pancreas and Other Tumoral Intraepithelial Neoplasms of Pancreatobiliary Tract: Recommendations of Verona Consensus Meeting.

  2016cited by this paper
• Overexpression of Nodal induces a metastatic phenotype in pancreatic cancer cells via the Smad2/3 pathway

  2015cited by this paper
• Ataxia-telangiectasia–Mutated Protein Kinase Levels Stratify Patients With Pancreatic Adenocarcinoma Into Prognostic Subgroups With Loss Being a Strong Indicator of Poor Survival

  2015cited by this paper
• Whole genomes redefine the mutational landscape of pancreatic cancer

  2015cited by this paper
• Increased expression of Nodal correlates with reduced patient survival in pancreatic cancer.

  2015cited by this paper
• American gastroenterological association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts.

  2015cited by this paper
• Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.

  2015cited by this paper
• BMP4 Promotes EMT and Mesodermal Commitment in Human Embryonic Stem Cells via SLUG and MSX2

  2014cited by this paper
• Supplemental Information TBX 3 Directs Cell-Fate Decision toward Mesendoderm

  2014cited by this paper
• ATM signalling and cancer

  2014cited by this paper
• The ATM protein kinase: regulating the cellular response to genotoxic stress, and more

  2013cited by this paper
• Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor.

  2013cited by this paper
• Nodal promotes aggressive phenotype via Snail-mediated epithelial-mesenchymal transition in murine melanoma.

  2013cited by this paper
• TBX3 Directs Cell-Fate Decision toward Mesendoderm

  2013cited by this paper
• Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis

  2013cited by this paper
• Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer

  2013cited by this paper
• Isolation, culture and genetic manipulation of mouse pancreatic ductal cells

  2013cited by this paper
• Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness

  2012cited by this paper
• Meta-Analysis of Gene Expression Signatures Defining the Epithelial to Mesenchymal Transition during Cancer Progression

  2012cited by this paper
• EMT and dissemination precede pancreatic tumor formation.

  2012cited by this paper
• The Pancreas Cancer Microenvironment

  2012cited by this paper
• Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

  2012cited by this paper
• DPEP1 Inhibits Tumor Cell Invasiveness, Enhances Chemosensitivity and Predicts Clinical Outcome in Pancreatic Ductal Adenocarcinoma

  2012cited by this paper
• Slug and Sox9 cooperatively determine the mammary stem cell state.

  2012cited by this paper
• Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma.

  2012cited by this paper
• ATM mutations in patients with hereditary pancreatic cancer.

  2012cited by this paper
• A Multi-Cancer Mesenchymal Transition Gene Expression Signature Is Associated with Prolonged Time to Recurrence in Glioblastoma

  2012cited by this paper
• Subtypes of Pancreatic Ductal Adenocarcinoma and Their Differing Responses to Therapy

  2011cited by this paper
• The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse.

  2011cited by this paper
• Cancer Statistics, 2010

  2010cited by this paper
• Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas.

  2010cited by this paper
• Transforming growth factor β regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM

  2010cited by this paper
• Telomeres are shortened in acinar-to-ductal metaplasia lesions associated with pancreatic intraepithelial neoplasia but not in isolated acinar-to-ductal metaplasias

  2010cited by this paper
• Advanced pancreatic carcinoma: current treatment and future challenges

  2010cited by this paper
• The combined status of ATM and p53 link tumor development with therapeutic response.

  2009cited by this paper
• Graded Smad2/3 Activation Is Converted Directly into Levels of Target Gene Expression in Embryonic Stem Cells

  2009cited by this paper
• The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs

  2009cited by this paper
• Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits

  2009cited by this paper
• Overexpression of bone morphogenetic protein 4 enhances the invasiveness of Smad4-deficient human colorectal cancer cells.

  2009cited by this paper
• Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2.

  2009cited by this paper
• ATM gene mutations result in both recessive and dominant expression phenotypes of genes and microRNAs.

  2008cited by this paper
• Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses

  2008cited by this paper
• Atm is a negative regulator of intestinal neoplasia

  2008cited by this paper
• A Mouse to Human Search for Plasma Proteome Changes Associated with Pancreatic Tumor Development

  2008cited by this paper
• BMP type I receptor inhibition reduces heterotopic ossification

  2008cited by this paper
• Complementary functions of ATM and H2AX in development and suppression of genomic instability

  2008cited by this paper
• Faithful activation of an extra‐bright red fluorescent protein in “knock‐in” Cre‐reporter mice ideally suited for lineage tracing studies

  2007cited by this paper
• ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage

  2007cited by this paper
• A Proteomic Analysis of Ataxia Telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) Substrates Identifies the Ubiquitin-Proteasome System as a Regulator for DNA Damage Checkpoints*

  2007cited by this paper
• The Intestinal Wnt/TCF Signature.

  2007cited by this paper
• Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer.

  2007cited by this paper
• A comparative study of methods for dynamic reverse-engineering of state models

  2007cited by this paper
• Atm-haploinsufficiency enhances susceptibility to carcinogen-induced mammary tumors.

  2006cited by this paper
• Inhibition of transforming growth factor-beta1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress.

  2006cited by this paper
• Cancer risks and mortality in heterozygous ATM mutation carriers.

  2005cited by this paper
• BMP signaling and early embryonic patterning.

  2005cited by this paper
• Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses.

  2005cited by this paper
• Smad4 Dependency Defines Two Classes of Transforming Growth Factor β (TGF-β) Target Genes and Distinguishes TGF-β-Induced Epithelial-Mesenchymal Transition from Its Antiproliferative and Migratory Responses

  2005cited by this paper
• Atm heterozygosity cooperates with loss of Brca1 to increase the severity of mammary gland cancer and reduce ductal branching.

  2005cited by this paper
• DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis

  2005cited by this paper
• Expression of ATM Protein and Its Relationship With p53 in Pancreatic Carcinoma With Tissue Array

  2004cited by this paper
• An Illustrated Consensus on the Classification of Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous Neoplasms

  2004cited by this paper
• Designing and implementing quality control for multi‐center screening of mutations in the ATM gene among women with breast cancer

  2003cited by this paper
• DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation

  2003cited by this paper
• Loss of atm sensitises p53-deficient cells to topoisomerase poisons and antimetabolites.

  2003cited by this paper
• Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.

  2003cited by this paper
• The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors

  2002cited by this paper
• Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer

  2002cited by this paper
• Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells.

  2002cited by this paper
• Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras.

  2001cited by this paper
• Pathology and genetics of tumors of the digestive system

  2001cited by this paper
• Z/AP, a double reporter for cre-mediated recombination.

  1999cited by this paper
• Heterozygous ATM mutations do not contribute to early onset of breast cancer

  1997cited by this paper
• Cancer statistics

  1989cited by this paper

• Cellular states associated with metastatic organotropism and survival in patients with pancreatic ductal adenocarcinoma

  2025cites this paper
• Long‐Term Survival With Olaparib Maintenance Therapy in Metastatic Pancreatic Carcinoma of a Patient Harboring Germline BRIP1 and ATM Mutations

  2025cites this paper
• Spatially resolved analysis of TGF/BMP signalling in pancreatic ductal adenocarcinoma by digital pathology identifies patient subgroups with adverse outcome

  2025influential citation
• Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics

  2025influential citation
• Phosphorylated BLM peptide acts as an agonist for DNA damage response

  2025cites this paper
• Targeted hotspot profiling reveals a functionally relevant mutation in bladder cancer.

  2025cites this paper
• Contemporary insights into the molecular mechanisms of development and genetic susceptibility to pancreatic cancer

  2025cites this paper
• Tumor microenvironment subtyping in pancreatic ductal adenocarcinoma: New avenues for personalized therapeutic strategies.

  2025cites this paper
• DNA Damage and Repair in Pancreatic Cancer—The Latest Findings

  2025cites this paper
• ATM inhibitors in cancer radiotherapy: Mechanisms, clinical development, and future directions.

  2025cites this paper
• Drivers of Pancreatic Cancer: Beyond the Big 4

  2025cites this paper
• Familial Pancreatic Cancer Research: Bridging Gaps in Basic Research and Clinical Application

  2024cites this paper
• Loss of tumor-derived SMAD4 enhances primary tumor growth but not metastasis following BMP4 signalling

  2024cites this paper
• Gastrointestinal Malignancy: Genetic Implications to Clinical Applications.

  2024cites this paper
• Targeting the ATM pathway in cancer: Opportunities, challenges and personalized therapeutic strategies.

  2024cites this paper
• ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer

  2023cites this paper
• Identification of ATM Mutation as a Potential Prognostic Biomarker for Immune Checkpoint Inhibitors Therapy.

  2023cites this paper
• Reduced expression of phosphorylated ataxia-telangiectasia mutated gene is related to poor prognosis and gemcitabine chemoresistance in pancreatic cancer

  2023cites this paper
• Somatic loss of ATM is a late event in pancreatic tumorigenesis

  2023cites this paper
• TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration

  2023cites this paper
• The Role of Genetic, Metabolic, Inflammatory, and Immunologic Mediators in the Progression of Intraductal Papillary Mucinous Neoplasms to Pancreatic Adenocarcinoma

  2023cites this paper
• The Landscape and Therapeutic Targeting of BRCA1, BRCA2 and Other DNA Damage Response Genes in Pancreatic Cancer

  2023cites this paper
• Genome-wide identification of A-to-I RNA editing events provides the functional implications in PDAC

  2023cites this paper
• Genetics, Genomics and Emerging Molecular Therapies of Pancreatic Cancer

  2023cites this paper
• ATM inhibitor KU60019 synergistically sensitizes lung cancer cells to topoisomerase II poisons by multiple mechanisms

  2023cites this paper
• Individualized therapy based on the combination of mini-PDX and NGS for a patient with metastatic AFP-producing and HER-2 amplified gastric cancer

  2022cites this paper
• Higher ATM expression in lymphoblastoid cell lines from centenarian compared with younger women

  2022cites this paper
• NEDD9 Restrains dsDNA Damage Response during Non-Small Cell Lung Cancer (NSCLC) Progression

  2022cites this paper
• Loss of tumor suppressor WWOX accelerates pancreatic cancer development through promotion of TGFβ/BMP2 signaling

  2022cites this paper
• DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities

  2022cites this paper
• CDKN2A-Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome

  2021cites this paper
• Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities

  2021cites this paper
• Beyond the Double-Strand Breaks: The Role of DNA Repair Proteins in Cancer Stem-Cell Regulation

  2021cites this paper
• Mechanisms of Cancer Cell Death: Therapeutic Implications for Pancreatic Ductal Adenocarcinoma

  2021cites this paper
• DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives

  2021influential citation
• Targeting BRCA and DNA Damage Repair Genes in GI Cancers: Pathophysiology and Clinical Perspectives

  2021influential citation
• Uncertain Beginnings: Acinar and Ductal Cell Plasticity in the Development of Pancreatic Cancer

  2021cites this paper
• Vom Tiermodell über humane Organoide in die Klinik

  2021cites this paper
• Modellsysteme in der gastroenterologischen Forschung

  2021cites this paper
• Hacking Pancreatic Cancer: Present and Future of Personalized Medicine

  2021cites this paper
• Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma

  2021cites this paper
• The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives

  2021cites this paper
• Targeted Therapies for Pancreatic Cancer: Overview of Current Treatments and New Opportunities for Personalized Oncology

  2021cites this paper
• Targeting DNA Damage Repair Mechanisms in Pancreas Cancer

  2021cites this paper
• Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration

  2021cites this paper
• Diverse and precision therapies open new horizons for patients with advanced pancreatic ductal adenocarcinoma.

  2021cites this paper
• Molecular subclassification of gastrointestinal cancers based on cancer stem cell traits

  2021cites this paper
• Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance

  2021cites this paper
• Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion

  2021influential citation
• DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives

  2020cites this paper
• ATM Serine/Threonine Kinase and its Role in Pancreatic Risk

  2020cites this paper
• ATM, ATR and DNA-PKcs kinases—the lessons from the mouse models: inhibition ≠ deletion

  2020cites this paper
• Pancreatic cancer-derived organoids – a disease modeling tool to predict drug response

  2020cites this paper
• Iron and Lipocalin-2 Modulate Cellular Responses in the Tumor Micro-environment of Pancreatic Ductal Adenocarcinoma

  2020cites this paper
• Abnormal expression of p-ATM/CHK2 in nasal extranodal NK/T cell lymphoma, nasal type, is correlated with poor prognosis

  2020cites this paper
• Prognostic Value of DNA Damage Response Genomic Alterations in Relapsed/Advanced Urothelial Cancer.

  2020cites this paper
• Cell polarity and oncogenesis: common mutations contribute to altered cellular polarity and promote malignancy

  2020cites this paper
• Blood-based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Pancreatic Cancer and its Value to Guide Clinical Treatment

  2020cites this paper
• An Immunological Glance on Pancreatic Ductal Adenocarcinoma

  2020cites this paper
• DNA damage checkpoint kinases in cancer

  2020cites this paper
• BAP1 is a haploinsufficient tumor suppressor linking chronic pancreatitis to pancreatic cancer in mice

  2020cites this paper
• Associations of novel variants in PIK3C3, INSR and MAP3K4 of the ATM pathway genes with pancreatic cancer risk.

  2020cites this paper
• Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer

  2020cites this paper
• Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy

  2020cites this paper
• UEG Week 2020 Oral Presentations

  2020cites this paper
• Alterations of DNA damage response genes correlate with response and overall survival in anti‐PD‐1/PD‐L1‐treated advanced urothelial cancer

  2020cites this paper
• Analysis of differentially expressed genes in oral epithelial cells infected with Fusobacterium nucleatum for revealing genes associated with oral cancer

  2020cites this paper
• Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy

  2019cites this paper
• Genetics and biology of pancreatic cancer and its precursor lesions: lessons learned from human pathology and mouse models

  2019cites this paper
• The Use of Genetically Engineered Mouse Models for Studying the Function of Mutated Driver Genes in Pancreatic Cancer

  2019cites this paper
• Treatment of pancreatic cancer-neoadjuvant treatment in borderline resectable/locally advanced pancreatic cancer.

  2019cites this paper
• Inhibition of ATM increases interferon signaling and sensitizes pancreatic cancer to immune checkpoint blockade therapy.

  2019cites this paper
• Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway

  2019cites this paper
• Low Expression of ATM Indicates a Poor Prognosis in Clear Cell Renal Cell Carcinoma.

  2019cites this paper
• Endogenously Expressed Antigens Bind Mammalian RNA via Cationic Domains that Enhance Priming of Effector CD8 T Cells by DNA Vaccination

  2019cites this paper
• SOX9 as One of the Central Units of Regulation Axis of Pancreas Embryogenesis and Cancer Progression

  2019cites this paper
• RAD51 is a potential marker for prognosis and regulates cell proliferation in pancreatic cancer

  2019cites this paper
• From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer

  2019cites this paper
• ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

  2019cites this paper
• SOX9 как одно из центральных звеньев оси регуляции эмбрионального развития и прогрессии рака поджелудочной железы

  2019cites this paper
• Increased Regeneration Following Stress-Induced Lung Injury in Bleomycin-Treated Chimeric Mice with CD44 Knockout Mesenchymal Cells

  2019cites this paper
• Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges

  2018cites this paper
• Advances in Molecular Profiling and Categorisation of Pancreatic Adenocarcinoma and the Implications for Therapy

  2018cites this paper
• 1 The circulating transcriptome as a source of 2 biomarkers for melanoma 3

  2018cites this paper
• The Circulating Transcriptome as a Source of Biomarkers for Melanoma

  2018cites this paper
• UEG Week 2018 Oral Presentations

  2018cites this paper
• Increased SOX9 Expression in Premalignant and Malignant Pancreatic Neoplasms

  2018cites this paper
• Precision medicine meets the DNA damage response in pancreatic cancer

  2018cites this paper
• New Developments in the Molecular Mechanisms of Pancreatic Tumorigenesis.

  2017cites this paper
• DNA-dependent protein kinase plays a central role in transformation of breast epithelial cells following alkylation damage

  2017cites this paper
• Sp1 phosphorylation by ATM downregulates BER and promotes cell elimination in response to persistent DNA damage

  2017cites this paper
• Understanding Disease Biology and Informing the Management of Pancreas Cancer With Preclinical Model Systems

  2017cites this paper
• Pericyte‐derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion

  2017cites this paper
• Reprogramming to pluripotency does not require transition through a primitive streak-like state

  2017cites this paper
• Cells of origin of pancreatic neoplasms

  2017cites this paper
• ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage.

  2017influential citation
• The depletion of ATM inhibits colon cancer proliferation and migration via B56γ2-mediated Chk1/p53/CD44 cascades.

  2017cites this paper
• ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer

  2017cites this paper
• Tbx3 fosters pancreatic cancer growth by increased angiogenesis and activin/nodal-dependent induction of stemness.

  2016cites this paper
• Direct interaction between miR-203 and ZEB2 suppresses epithelial-mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance.

  2016cites this paper