16 results on '"Anne-Sophie Lamort"'
Search Results
2. Cathepsin C inhibition as a potential treatment strategy in cancer
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Anne-Sophie Lamort, Artur Giełdoń, Aö Yildirim, Moez Rhimi, Céline Beauvillain, Dieter E. Jenne, Georgios T. Stathopoulos, Roxane Domain, Brice Korkmaz, Ralph Kettritz, Bernardo, Elizabeth, Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig Maximilian University [Munich] (LMU), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), University of Gdańsk (UG), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
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Cancer ,Inflammation ,Inhibitor ,Neutrophil ,Protease ,Treatment Strategy ,Proteases ,Neutrophils ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Antineoplastic Agents ,Cathepsin G ,Biology ,medicine.disease_cause ,Biochemistry ,Extracellular Traps ,Cathepsin C ,Protein Structure, Secondary ,chemistry.chemical_compound ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Proteinase 3 ,Neoplasms ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Pharmacology ,Proteolytic enzymes ,Neutrophil extracellular traps ,medicine.disease ,Protein Structure, Tertiary ,Treatment strategy ,chemistry ,Cancer research ,Inflammation Mediators ,Serine Proteases ,Carcinogenesis - Abstract
International audience; Epidemiological studies established an association between chronic inflammation and higher risk of cancer. Inhibition of proteolytic enzymes represents a potential treatment strategy for cancer and prevention of cancer metastasis. Cathepsin C (CatC) is a highly conserved lysosomal cysteine dipeptidyl aminopeptidase required for the activation of pro-inflammatory neutrophil serine proteases (NSPs, elastase, proteinase 3, cathepsin G and NSP-4). NSPs are locally released by activated neutrophils in response to pathogens and non-infectious danger signals. Activated neutrophils also release neutrophil extracellular traps (NETs) that are decorated with several neutrophil proteins, including NSPs. NSPs are not only NETs constituents but also play a role in NET formation and release. Although immune cells harbor large amounts of CatC, additional cell sources for this protease exists. Upregulation of CatC expression was observed in different tissues during carcinogenesis and correlated with metastasis and poor patient survival. Recent mechanistic studies indicated an important interaction of tumor-associated CatC, NSPs, and NETs in cancer development and metastasis and suggested CatC as a therapeutic target in a several cancer types. Cancer cell-derived CatC promotes neutrophil recruitment in the inflammatory tumor microenvironment. Because the clinical consequences of genetic CatC deficiency in humans resulting in the elimination of NSPs are mild, small molecule inhibitors of CatC are assumed as safe drugs to reduce the NSP burden. Brensocatib, a nitrile CatC inhibitor is currently tested in a phase 3 clinical trial as a novel anti-inflammatory therapy for patients with bronchiectasis. However, recently developed CatC inhibitors possibly have protective effects beyond inflammation. In this review, we describe the pathophysiological function of CatC and discuss molecular mechanisms substantiating pharmacological CatC inhibition as a potential strategy for cancer treatment.
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- 2021
3. Tumor-secreted versican co-opts myeloid IKKβ during metastasis
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Fiona E. Yull, G Skiadas, David Brunn, Michael Lindner, M Spella, Giannoula Ntaliarda, Rajkumar Savai, Weiss Sa, Mario A.A. Pepe, Rudolf Hatz, Georgios T. Stathopoulos, Ioanna Giopanou, Petrera A, Ina Koch, Bouloukou E, Timothy S. Blackwell, Antonia Marazioti, Malamati Vreka, Georgia A. Giotopoulou, Ioannis Lilis, Dieter E. Jenne, K. Arendt, Juergen Behr, Stefanie M. Hauck, and Anne-Sophie Lamort
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Tumor microenvironment ,Myeloid ,biology ,Chemistry ,Interleukin ,IκB kinase ,medicine.disease ,Metastasis ,medicine.anatomical_structure ,Cancer cell ,biology.protein ,medicine ,Cancer research ,Versican ,Gene silencing - Abstract
The mechanisms tumor cells use to hijack the immune system are largely uncharted. Here we used bioluminescent nuclear factor (NF)-κB reporter mice and macrophages to discover that metastatic tumors trigger NF-κB activation in host macrophages, dependent on mutant KRAS signaling and delivered via secretory versican. Versican activates NF-κB in tumor-associated macrophages via inhibitor of NF-κB kinase (IKK) β, resulting in release of interleukin (IL)-1β into the tumor microenvironment. Versican silencing in cancer cells or conditional IKKβ deletion in macrophages prevents myeloid NF-κB activation and metastasis. Versican is overexpressed and/or mutated in human cancers and metastatic effusions with KRAS mutations, predicts poor survival, can aid in the development of diagnostic platforms for pleural metastasis, and is druggable via toll-like receptor (TLR) 1/2 inhibition. The data indicate a cardinal role for tumor-derived versican in establishing cross-talk with macrophage IKKβ during metastasis and may foster the development of new therapies and diagnostic tools.
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- 2021
4. Tobacco chemical-induced mouse lung adenocarcinoma cell lines pin the prolactin orthologue proliferin as a lung tumour promoter
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Helen Papadaki, Theodora Agalioti, Anastasios D. Giannou, Magda Spella, Anne Sophie Lamort, Nikolaos I. Kanellakis, Georgios T. Stathopoulos, Spyridon Champeris Tsaniras, Mario A.A. Pepe, I Psallidas, Stavros Taraviras, Ioanna Giopanou, Ioannis Lilis, Dimitra E. Zazara, Antonia Marazioti, and Kristina A. M. Arendt
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Carcinogenesis ,Thyroid Nuclear Factor 1 ,Adenocarcinoma of Lung ,Biology ,medicine.disease_cause ,Urethane ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Tobacco ,medicine ,Animals ,Diethylnitrosamine ,Carcinogen ,Mutation ,Mucin ,General Medicine ,medicine.disease ,Prolactin ,Gene Expression Regulation, Neoplastic ,Transplantation ,Disease Models, Animal ,Genes, ras ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Carcinogens ,Cancer research ,Adenocarcinoma ,KRAS ,Tumor Suppressor Protein p53 - Abstract
Lung adenocarcinoma (LADC) is the leading cause of cancer death worldwide. Nevertheless, syngeneic mouse models of the disease are sparse, and cell lines suitable for transplantable and immunocompetent mouse models of LADC remain unmet needs. We established multiple mouse LADC cell lines by repeatedly exposing two mouse strains (FVB, Balb/c) to the tobacco carcinogens urethane or diethylnitrosamine and by culturing out the resulting lung tumours for prolonged periods of time. Characterization of the resulting cell lines (n = 7) showed that they were immortal and phenotypically stable in vitro, and oncogenic, metastatic and lethal in vivo. The primary tumours that gave rise to the cell lines, as well as secondary tumours generated by transplantation of the cell lines, displayed typical LADC features, such as glandular architecture and mucin and thyroid transcription factor 1 expression. Moreover, these cells exhibited marked molecular similarity with human smokers’ LADC, including carcinogen-specific Kras point mutations (KrasQ61R in urethane- and KrasQ61H in diethylnitrosamine-triggered cell lines) and Trp53 deletions and displayed stemness features. Interestingly, all cell lines overexpressed proliferin, a murine prolactin orthologue, which functioned as a lung tumour promoter. Furthermore, prolactin was overexpressed and portended poor prognosis in human LADC. In conclusion, we report the first LADC cell lines derived from mice exposed to tobacco carcinogens. These cells closely resemble human LADC and provide a valuable tool for the functional investigation of the pathobiology of the disease.
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- 2019
5. Comprehensive clinical profiling of the Gauting locoregional lung adenocarcinoma donors
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Serge Guyétant, Jürgen Behr, Yves Courty, Kristina A. M. Arendt, Agnès Petit-Courty, Sylvain Marchand-Adam, Valérie Gissot, Anne-Sophie Lamort, Ina Koch, Jan‐Christian Kaiser, Georgios T. Stathopoulos, Ioanna Giopanou, Maria Oplopoiou, Michael Lindner, Ioannis Lilis, Martin E. Eichhorn, Rudolf Hatz, Giannoula Ntaliarda, Mario A.A. Pepe, Laura V. Klotz, Anja Stowasser, Alicia Morresi-Hauf, Sabine J. Behrend, Ludwig Maximilians University of Munich, German Center for Lung Research, Comprehensive pneumology center, Partenaires INRAE, University Hospital, German Centre for Lung Research, Institut National de la Santé et de la Recherche Médicale (INSERM), University-Hospital Munich-Großhadern [München], Heidelberg University, University of Patras, Alexander Fleming Biomedical Sciences Research Center, Asklepios Medical Center, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours, Centre Hospitalier Régional Universitaire de Tours (CHRU de Tours), Asklepios Lung Clinic Gauting, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Ludwig-Maximilians University [Munich] (LMU), and ProdInra, Migration
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0301 basic medicine ,Research design ,Male ,Cancer Research ,Lung Neoplasms ,Death risk ,Pneumologie et système respiratoire ,LADC ,lung adenocarcinoma ,obstruction ,smoking ,survival ,Pulmonary Surgical Procedures ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,0302 clinical medicine ,Recurrence ,Germany ,Medicine ,Prospective Studies ,Cancer ,Original Research ,Curative intent ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,résection ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cohort ,Adenocarcinoma ,Female ,Lung resection ,medicine.medical_specialty ,adénocarcinome ,Médecine humaine et pathologie ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Adenocarcinoma of Lung ,lcsh:RC254-282 ,Time-to-Treatment ,03 medical and health sciences ,FEV1/FVC ratio ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,Humans ,tabagisme ,Radiology, Nuclear Medicine and imaging ,Mortality ,Pulmonology and respiratory tract ,Aged ,Neoplasm Staging ,Lung ,business.industry ,Clinical Cancer Research ,medicine.disease ,030104 developmental biology ,poumon ,[SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,Human health and pathology ,Ladc ,Lung Adenocarcinoma ,Obstruction ,Smoking ,Survival ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; A comprehensive characterization of lung adenocarcinoma (LADC) clinical features is currently missing. We prospectively evaluated Caucasian patients with early-stage LADC. Patients with LADC diagnosed between 2011 and 2015 were prospectively assessed for lung resection with curative intent. Fifty clinical, pathologic, radiologic, and molecular variables were recorded. Patients were followed till death/study conclusion. The main findings were compared to a separate cohort from France. Of 1943 patients evaluated, 366 were enrolled (18.8%; 181 female; 75 never-smokers; 28% of registered Bavarian cases over the study period). Smoking and obstruction were significantly more prevalent in GLAD compared with adult Bavarians (P < 0.0001). Ever-smoker tumors were preferentially localized to the upper lobes. We observed 120 relapses and 74 deaths over 704 cumulative follow-up years. Median overall and disease-free survival were >7.5 and 3.6 years, respectively. Patients aged 65 years, resected >60 days postdiagnosis, with abnormal FVC/DLCO VA , N2/N3 stage, or solid histology had significantly decreased survival estimates. These were fit into a weighted locoregional LADC death risk score that outperformed pTNM7 in predicting survival in the GLAD and in our second cohort. We define the clinical gestalt of locoregional LADC and provide a new clinical tool to predict survival, findings that may aid future management and research design
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- 2019
6. Mutational RNA signatures in environmentally-induced lung adenocarcinoma
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Giannoula Ntaliarda, Ioannis Lillis, Georgios T. Stathopoulos, Anne-Sophie Lamort, Mario A.A. Pepe, Sabine J. Behrend, Georgia A. Giotopoulou, and Magda Spella
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Lung ,business.industry ,Point mutation ,RNA ,medicine.disease ,medicine.disease_cause ,medicine.anatomical_structure ,Gene expression ,medicine ,Cancer research ,Adenocarcinoma ,KRAS ,Lung cancer ,business ,Gene ,Carcinogen - Abstract
Introduction: Lung adenocarcinoma (LUAD) is the most frequent lung cancer in non-smokers. Although carcinogens other than smoking (i.e., radiation) likely cause LUAD, their molecular imprints are obscure. Objectives: To define the molecular imprints of smoking, its carcinogens, and radiation in LUAD RNA. Materials and Methods: FVB mice were exposed to tobacco smoke (500 mg/m3; 2 hrs/day; 5 months on/5 months off), its chemicals ethyl carbamate (1 g/Kg), diethylnitrosamine (20 mg/Kg), and methylnitrosourea (50 mg/Kg), or X-irradiation (15 Gy X-rays delivered to a 100 mm3 tissue voxel of the right upper lobe). Total lung tumor RNA was extracted using Trizol/RNAeasy, was analyzed on an Illumina HiSeq4000, and was interrogated employing STAR, DeSeqR, Pathvisio, GSEA, Samtools, SnpEff, and R*. Results: FVB mice developed LUAD in response to the carcinogens used. RNAseq of tumor tissues provided robust transcript abundance and sequence information, including single nucleotide variation at the mononucleotide, trinucleotide, gene, and chromosome levels, as well as insertions and deletions. The five different carcinogens produced markedly distinct mutational imprints on the exposed tissues. Interestingly, the signatures of smoking and its carcinogens were highly similar, contained KRAS and other point mutations, and were enriched in human KRAS-mutant LUAD, while the signatures of irradiated tissues displayed EGFR point mutations, a preponderance of transversions, and a distinct gene expression set. Conclusions: Bulk RNAseq of environmentally-induced mouse tumors can reveal carcinogenic exposures and causes. We are currently working to identify cellular origin-restricted signatures and to translate murine imprints to human LUAD.
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- 2021
7. Caspase-11 and AIM2 inflammasome are involved in smoking-induced COPD and lung adenocarcinoma
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Georgios T. Stathopoulos, Chiara Colarusso, Anne-Sophie Lamort, Fiorentina Roviezzo, Ida Cerqua, Aldo Pinto, Michela Terlizzi, and Rosalinda Sorrentino
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0301 basic medicine ,03 medical and health sciences ,AIM2 ,0302 clinical medicine ,inflammasome ,medicine ,COPD ,Lung cancer ,Survival rate ,Lung ,business.industry ,Hazard ratio ,lung inflammation ,Inflammasome ,medicine.disease ,Copd ,Lung Cancer ,Lung Inflammation ,Smoke ,respiratory tract diseases ,lung cancer ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,smoke ,030220 oncology & carcinogenesis ,Immunology ,Adenocarcinoma ,business ,medicine.drug ,Research Paper - Abstract
Cigarette smoking is the leading risk factor for COPD and lung cancer establishment. Epidemiologically, COPD patients are 6.35 times more likely to develop lung cancer. To mimic COPD, we exposed mice to nose-only cigarette smoke and used human samples of lung adenocarcinoma patients according to the smoking and COPD status. Smoking C57Bl/6N mice had higher enlargement of alveoli, deposition of collagen and mucus production, associated to the release of IL-1-like cytokines, such as IL-1α and IL-1β at early time points and IL-18 at later time points. AIM2 expression was higher in lung recruited dendritic cells and macrophages in smoking mice, associated to the activation of caspase-11, rather than caspase-1. In support,129Sv mice, which are dysfunctional for caspase-11, had lower collagen deposition and mucus production, associated to lower release of IL-1-like and fibrotic TGFβ. Interestingly, higher expression of AIM2 in non-cancerous tissue of smoking COPD adenocarcinoma patients was correlated to a higher hazard ratio of poor survival rate than in patients who presented lower levels of AIM2. We found that AIM2 inflammasome is at the crossroad between COPD and lung cancer in that its higher presence is correlated to lower survival rate of smoking COPD adenocarcinoma patients.
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- 2021
8. KRASsignalling in malignant pleural mesothelioma
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Michael Lindner, Marianthi Iliopoulou, Mario A.A. Pepe, Ina Koch, Sophia G. Antimisiaris, Marc Grégoire, I Psallidas, Rudolf Hatz, Ioannis Lilis, Anthi C. Krontira, M Spella, Darcy E. Wagner, Georgios T. Stathopoulos, C. M. Hackl, A. Marazioti, Ioanna Giopanou, Helen Papadaki, S. Deshayes, Malamati Vreka, Christophe Blanquart, Juergen Behr, and Anne-Sophie Lamort
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BAP1 ,Pleural effusion ,Point mutation ,Pleural cavity ,Biology ,medicine.disease_cause ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,CDKN2A ,medicine ,Cancer research ,Ectopic expression ,KRAS ,Gene - Abstract
Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to the development of pleural effusion and death. MPM harbours loss-of-function mutations in genes likeBAP1, NF2, CDKN2A, andTP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here we show that a significant proportion of human MPM harbour point mutations and copy number alterations in theKRASproto-oncogene. These mutations are likely pathogenic, since ectopic expression of mutantKRASG12Din the pleural mesothelium of conditional mice causes MPM. Murine MPM cell lines derived from these tumours carry the initiatingKRASG12Dlesions, secondaryBap1alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate thatKRASmutations likely play an important and underestimated role in MPM, which warrants further exploration.
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- 2020
9. LSC - 2020 - Transcriptome signatures of tobacco carcinogens hint the alteration of TAF6 as a specific feature in smokers lung cancer
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Georgos Stathopoulos, Anne-Sophie Lamort, and Mario A.A. Pepe
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business.industry ,Smokers lung ,Cancer ,RNA ,Computational biology ,medicine.disease ,Genome ,Human lung ,Transcriptome ,medicine.anatomical_structure ,medicine ,Adenocarcinoma ,business ,Carcinogen - Abstract
Background: Sequencing studies of human lung adenocarcinoma(LUAD) and carcinogens induced LUAD in animal models showed how the different mutational processes leave their specific signatures in the genome. Despite the intense effort, those signatures were extracted from heterogeneous tumor tissues and underestimated the expressed single nucleotide variation (eSNV). Aim: To define transcriptome mutational signature in carcinogen-induced LUAD, we investigated the raised mutations in transcriptome of different carcinogen-induced LUAD cell lines and compared those signatures with LUAD samples. Method: We used urethane and diethylnitrosamine, tobacco carcinogens, to induce LUAD in different strains of inbred mice and established cell lines thereof(n = 13).we selected a collection of 16 human LUAD samples (8 smokers and 8never smokers). RNA was subjected to RNAseq. Data were analyzed for the detection of eSNV. Results: In 14550 eSNV, we observed 15 recurring eSNV across all LUAD cell lines. As for the cell lines, we retrieved the mutational spectrum across the transcriptomes of our human samples. To conclude our validation of the tobacco-carcinogens transcriptome signature, we compared the presence of those in the smoker and never-smoker samples. We identified TAF6 alteration to be present only in smokers. Conclusion: We predict that transcriptome based approach on the mutational signature of carcinogens-induced cell lines can be applied to define signatures of alteration scalable to human scenarios. Moreover, our study defined the alteration of a new oncosoppressor, TAF6, in the panorama of smokers lung adenocarcinoma that deserves further investigation.
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- 2020
10. Molecular hallmarks of smoking in the Gauting lung adenocarcinoma donors
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Giannoula Ntaliarda, Mario A.A. Pepe, Georgios T. Stathopoulos, Ina Koch, Magda Spella, Ioannis Lilis, Jürgen Behr, Willem Kujawa, Rudolf Hatz, Michael Lindner, Anne-Sophie Lamort, and Sabine J. Behrend
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Lung ,medicine.anatomical_structure ,business.industry ,Cancer research ,Medicine ,Adenocarcinoma ,business ,medicine.disease - Published
- 2020
11. Club cells form lung adenocarcinomas and maintain the alveoli of adult mice
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Vassilis Aidinis, Malamati Vreka, Laura V. Klotz, Yuanyuan Chen, Fani Roumelioti, Rocio Sotillo, Dimitrios Toumpanakis, Vasileios Armenis, Spyros Zakynthinos, Anastasios D. Giannou, Magda Spella, Anne-Sophie Lamort, Vassiliki Karavana, Georgios T. Stathopoulos, Antonia Marazioti, Mario A.A. Pepe, Darcy E. Wagner, Kristina A. M. Arendt, Ioannis Lilis, Nikolaos I. Kanellakis, Dimitra E. Zazara, Ioanna Giopanou, and Maria Armaka
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0301 basic medicine ,Mouse ,medicine.disease_cause ,Tobacco smoke ,Mice ,0302 clinical medicine ,Biology (General) ,Cancer Biology ,General Neuroscience ,General Medicine ,respiratory system ,3. Good health ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Medicine ,KRAS ,Research Article ,Human ,Cell Survival ,QH301-705.5 ,Science ,urethane ,Adenocarcinoma of Lung ,Respiratory Mucosa ,Lung injury ,General Biochemistry, Genetics and Molecular Biology ,Alveolar cells ,chemical carcinogenesis ,03 medical and health sciences ,Tobacco Smoking ,medicine ,Animals ,airway transcriptome ,Lung cancer ,Carcinogen ,Cell Proliferation ,Lung ,General Immunology and Microbiology ,business.industry ,Airway Transcriptome ,Cell Biology ,Chemical Carcinogenesis ,Lung Adenocarcinoma ,Urethane ,Epithelial Cells ,Environmental Exposure ,medicine.disease ,lung adenocarcinoma ,respiratory tract diseases ,Pulmonary Alveoli ,Disease Models, Animal ,030104 developmental biology ,Carcinogens ,Cancer research ,business ,Carcinogenesis - Abstract
Lung cancer and chronic lung diseases impose major disease burdens worldwide and are caused by inhaled noxious agents including tobacco smoke. The cellular origins of environmental-induced lung tumors and of the dysfunctional airway and alveolar epithelial turnover observed with chronic lung diseases are unknown. To address this, we combined mouse models of genetic labeling and ablation of airway (club) and alveolar cells with exposure to environmental noxious and carcinogenic agents. Club cells are shown to survive KRAS mutations and to form lung tumors after tobacco carcinogen exposure. Increasing numbers of club cells are found in the alveoli with aging and after lung injury, but go undetected since they express alveolar proteins. Ablation of club cells prevents chemical lung tumors and causes alveolar destruction in adult mice. Hence club cells are important in alveolar maintenance and carcinogenesis and may be a therapeutic target against premalignancy and chronic lung disease., eLife digest The deadliest form of lung cancer is called lung adenocarcinoma, or LUAD. Tobacco chemicals often cause the disease by damaging the genetic information of lung cells. The damage leads to harmful changes in the DNA sequence which prompt the cells to form tumors. For instance, the most common of these changes takes place in a gene called KRAS. However, it is still unclear exactly which type of lung cells are more likely to develop into a tumor. In the lungs, airway epithelial cells cover the inside of the passages that bring the air inside little sacks called alveoli, which are lined by alveolar cells. Previous studies have used genetic methods to switch on the KRAS mutation in different compartments of the mouse lung. This showed that groups of airway cells, of alveolar cells, and of a class of cells located at the junction between airways and alveoli could all give rise to cancer. However, these experiments did not examine how tobacco chemicals could give rise to tumors in different groups of lung cells. Here, Spella et al. triggered LUAD in adult mice by exposing them to the toxic chemicals found in tobacco smoke, but without making any change to the KRAS gene. These mice also had genetically engineered reporters that could be used to deduce where the resulting tumors came from. DNA sequencing showed that the airway epithelial cells gained KRAS mutations after the chemical treatment. When the airway epithelial cells were experimentally removed before the treatments with tobacco chemicals, these mice did not get LUAD tumors. Spella et al. also observed that the tobacco-induced tumors came from the epithelial cells in the airways, and not from the cells in the alveoli. Moreover, when the lung was damaged, airway cells could move to the alveoli and start adopting the identity of alveolar cells, thereby replenishing this population. Together, these experiments imply that tobacco-induced LUAD starts in the airway epithelial cells. These findings suggest that airway epithelial cells could be targeted to stop lung cancer early on. Further studies should also examine how airway epithelial cells can transition to look more like alveolar cells when the lungs get harmed.
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- 2019
12. Osteopontin drives KRAS-mutant lung adenocarcinoma
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Nikolaos I. Kanellakis, Davina Camargo Madeira Simoes, Georgios T. Stathopoulos, Anne-Sophie Lamort, Theodora Agalioti, Ioannis Psallidas, Vily Panoutsakopoulou, Ioannis Kalomenidis, Anastasios D. Giannou, Dimitra E. Zazara, Magda Spella, Ioannis Lilis, Charalampos Moschos, Sophia Magkouta, Ioanna Giopanou, Antonia Marazioti, and Vassilios Papaleonidopoulos
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Angiogenesis ,Carcinogenesis ,B100 ,Cre recombinase ,Adenocarcinoma of Lung ,Biology ,medicine.disease_cause ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Kras ,Spp1 ,Lung Cancer ,Survival ,Urethane ,medicine ,Animals ,Humans ,Osteopontin ,Lung cancer ,Lung ,Smoking ,General Medicine ,Neoplasms, Experimental ,A300 ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,HEK293 Cells ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Cancer research ,Adenocarcinoma ,KRAS - Abstract
Increased expression of osteopontin (secreted phosphoprotein 1, SPP1) is associated with aggressive human lung adenocarcinoma (LADC), but its function remains unknown. Our aim was to determine the role of SPP1 in smoking-induced LADC. We combined mouse models of tobacco carcinogen-induced LADC, of deficiency of endogenous Spp1 alleles, and of adoptive pulmonary macrophage reconstitution to map the expression of SPP1 and its receptors and determine its impact during carcinogenesis. Co-expression of Spp1 and mutant KrasG12C in benign cells was employed to investigate SPP1/KRAS interactions in oncogenesis. Finally, intratracheal adenovirus encoding Cre recombinase was delivered to LSL.KRASG12D mice lacking endogenous or overexpressing transgenic Spp1 alleles. SPP1 was overexpressed in experimental and human LADC and portended poor survival. In response to two different smoke carcinogens, Spp1-deficient mice developed fewer and smaller LADC with decreased cellular survival and angiogenesis. Both lung epithelial- and macrophage-secreted SPP1 drove tumor-associated inflammation, while epithelial SPP1 promoted early tumorigenesis by fostering the survival of KRAS-mutated cells. Finally, loss and overexpression of Spp1 was, respectively, protective and deleterious for mice harboring KRASG12D-driven LADC. Our data support that SPP1 is functionally involved in early stages of airway epithelial carcinogenesis driven by smoking and mutant KRAS and may present an important therapeutic target.
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- 2019
13. Dual airway and alveolar contributions to adult lung homeostasis and carcinogenesis
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Laura V. Klotz, Antonia Marazioti, Darcy E. Wagner, Maria Armaka, Mario A.A. Pepe, Ioannis Lilis, Georgios T. Stathopoulos, Vasileios Armenis, Anne-Sophie Lamort, Fani Roumelioti, Yuanyuan Chen, Ioanna Giopanou, Nikolaos I. Kanellakis, Dimitra E. Zazara, Vassilis Aidinis, Kristina A. M. Arendt, Malamati Vreka, Vassiliki Karavana, Spyros Zakynthinos, Dimitrios Toumpanakis, Rocio Sotillo, Anastasios D. Giannou, and Magda Spella
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0303 health sciences ,Lung ,business.industry ,respiratory system ,medicine.disease_cause ,medicine.disease ,respiratory tract diseases ,3. Good health ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Adenocarcinoma ,KRAS ,Respiratory system ,Lung cancer ,Carcinogenesis ,business ,Homeostasis ,030304 developmental biology - Abstract
Lung adenocarcinoma (LUAD) and chronic lung diseases caused by smoking and environmental noxious agents are the deadliest diseases worldwide, sharing a partially charted pathobiology of dysfunctional alveolar repair. Here we sought to identify the respiratory epithelial dynamics and molecular signatures participating in adult lung maintenance and chemical carcinogenesis. We employed novel mouse models of respiratory epithelial marking and ablation, a battery of pulmonary toxins and carcinogens, experimental protocols of carcinogen-induced LUAD, tobacco carcinogen-induced LUAD cell lines, and human transcriptomic data and identified a prominent involvement of airway molecular programs in alveolar maintenance and carcinogen-induced LUAD. The airway-specific transcriptomic signature was redistributed to the alveoli after toxic and carcinogenic insults and resulted in marked contributions of airway-labeled cells to injury-recovered alveoli and LUAD. Airway cells maintained Kras mutations and therefore possibly contributed to lung cancer initiation, while LUAD were spatially linked to neighboring airways. Transcriptomic profiling of carcinogen-induced murine and human LUAD revealed enrichment in airway signatures, while ablation of airway cells distorted alveolar structure and function and protected mice from LUAD development. Collectively, these results indicate that airway cells and/or transcriptomic signatures are essential for alveolar maintenance and LUAD development.
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- 2019
14. Osteopontin as a link between inflammation and cancer: The thorax in the spotlight
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Georgios T. Stathopoulos, Ioannis Psallidas, Ioanna Giopanou, and Anne-Sophie Lamort
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OPN ,Inflammation ,Review ,Metastasis ,Extracellular matrix ,Opn ,Spp1 ,Lung Cancer ,Secreted Phosphoprotein 1 ,Mediator ,stomatognathic system ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Osteopontin ,Lung cancer ,lcsh:QH301-705.5 ,biology ,business.industry ,Cancer ,General Medicine ,medicine.disease ,lung cancer ,lcsh:Biology (General) ,Cancer research ,biology.protein ,medicine.symptom ,Wound healing ,business ,secreted phosphoprotein 1 ,SPP1 - Abstract
The glycoprotein osteopontin (OPN) possesses multiple functions in health and disease. To this end, osteopontin has beneficial roles in wound healing, bone homeostasis, and extracellular matrix (ECM) function. On the contrary, osteopontin can be deleterious for the human body during disease. Indeed, osteopontin is a cardinal mediator of tumor-associated inflammation and facilitates metastasis. The purpose of this review is to highlight the importance of osteopontin in malignant processes, focusing on lung and pleural tumors as examples.
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- 2019
15. Tumor-derived granulocyte chemotactic protein 2 cooperates with neutrophil proteinase 3 to drive lung adenocarcinoma
- Author
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Dieter E. Jenne, M Spella, S.A. Weiß, L Klotz, Giannoula Ntaliarda, Marina Lianou, K. Arendt, Anne-Sophie Lamort, Georgios T. Stathopoulos, Mario A.A. Pepe, V. Armenis, Maria Oplopoiou, A Marazioti, I Lillis, K Kauka, Georgia A. Giotopoulou, and Ioanna Giopanou
- Subjects
Lung ,medicine.anatomical_structure ,business.industry ,Proteinase 3 ,Chemokine CXCL6 ,Cancer research ,Medicine ,Adenocarcinoma ,Tumor-Derived ,business ,medicine.disease - Published
- 2018
16. Alteration patterns of tobacco carcinogens in lung adenocarcinoma reveal novel KRAS-addicted candidate oncogenes
- Author
-
Georgios T. Stathopoulos, Francesco Pelizza, Anne-Sophie Lamort, Nikolaos I. Kanellakis, and Mario A.A. Pepe
- Subjects
Lung ,medicine.anatomical_structure ,business.industry ,Cancer research ,Medicine ,Adenocarcinoma ,KRAS ,business ,medicine.disease ,medicine.disease_cause ,Carcinogen - Published
- 2018
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