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Your search keyword '"Del Monte-Nieto G"' showing total 6 results
Start Over Author "Del Monte-Nieto G" Topic signal transduction
6 results on '"Del Monte-Nieto G"'

1. Intravital Imaging to Monitor Therapeutic Response in Moving Hypoxic Regions Resistant to PI3K Pathway Targeting in Pancreatic Cancer.

Author

Conway JRW, Warren SC, Herrmann D, Murphy KJ, Cazet AS, Vennin C, Shearer RF, Killen MJ, Magenau A, Mélénec P, Pinese M, Nobis M, Zaratzian A, Boulghourjian A, Da Silva AM, Del Monte-Nieto G, Adam ASA, Harvey RP, Haigh JJ, Wang Y, Croucher DR, Sansom OJ, Pajic M, Caldon CE, Morton JP, and Timpson P

Subjects
Animals, Benzamides, Cell Line, Tumor, Drug Therapy, Combination, Female, Fluorescence Resonance Energy Transfer, Humans, Hypoxia, Intravital Microscopy methods, Mice, Mice, Inbred BALB C, Morpholines pharmacology, Morpholines therapeutic use, Nanoparticles chemistry, Nitroimidazoles pharmacology, Nitroimidazoles therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Phosphoramide Mustards pharmacology, Phosphoramide Mustards therapeutic use, Proto-Oncogene Proteins c-akt metabolism, Pyrimidines, Transplantation, Heterologous, Tumor Microenvironment, Drug Resistance, Neoplasm drug effects, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction drug effects
Abstract

Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Published
2018
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2. Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1.

Author

Wang Y, Wu B, Lu P, Zhang D, Wu B, Varshney S, Del Monte-Nieto G, Zhuang Z, Charafeddine R, Kramer AH, Sibinga NE, Frangogiannis NG, Kitsis RN, Adams RH, Alitalo K, Sharp DJ, Harvey RP, Stanley P, and Zhou B

Subjects
Animals, Cell Proliferation genetics, Coronary Artery Disease physiopathology, Echocardiography, Fucosyltransferases deficiency, Intracellular Signaling Peptides and Proteins deficiency, Intracellular Signaling Peptides and Proteins genetics, Membrane Proteins deficiency, Membrane Proteins genetics, Mice, Inbred C57BL, Mice, Knockout, Vascular Endothelial Growth Factor Receptor-2 deficiency, Vascular Endothelial Growth Factor Receptor-2 genetics, Vascular Endothelial Growth Factor Receptor-3 deficiency, Vascular Endothelial Growth Factor Receptor-3 genetics, Coronary Artery Disease genetics, Fucosyltransferases genetics, Neovascularization, Physiologic genetics, Signal Transduction genetics
Abstract

Coronary artery anomalies may cause life-threatening cardiac complications; however, developmental mechanisms underpinning coronary artery formation remain ill-defined. Here we identify an angiogenic cell population for coronary artery formation in mice. Regulated by a DLL4/NOTCH1/VEGFA/VEGFR2 signaling axis, these angiogenic cells generate mature coronary arteries. The NOTCH modulator POFUT1 critically regulates this signaling axis. POFUT1 inactivation disrupts signaling events and results in excessive angiogenic cell proliferation and plexus formation, leading to anomalous coronary arteries, myocardial infarction and heart failure. Simultaneous VEGFR2 inactivation fully rescues these defects. These findings show that dysregulated angiogenic precursors link coronary anomalies to ischemic heart disease.Though coronary arteries are crucial for heart function, the mechanisms guiding their formation are largely unknown. Here, Wang et al. identify a unique, endocardially-derived angiogenic precursor cell population for coronary artery formation in mice and show that a DLL4/NOTCH1/VEGFA/VEGFR2 signaling axis is key for coronary artery development.

Published
2017
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3. Sequential Ligand-Dependent Notch Signaling Activation Regulates Valve Primordium Formation and Morphogenesis.

Author

MacGrogan D, D'Amato G, Travisano S, Martinez-Poveda B, Luxán G, Del Monte-Nieto G, Papoutsi T, Sbroggio M, Bou V, Gomez-Del Arco P, Gómez MJ, Zhou B, Redondo JM, Jiménez-Borreguero LJ, and de la Pompa JL

Subjects
Adaptor Proteins, Signal Transducing, Animals, Calcium-Binding Proteins, Epithelial-Mesenchymal Transition, ErbB Receptors metabolism, Heparin-binding EGF-like Growth Factor metabolism, Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics, Immunoglobulin J Recombination Signal Sequence-Binding Protein metabolism, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Jagged-1 Protein genetics, Jagged-1 Protein metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mitral Valve abnormalities, Mitral Valve embryology, Receptor, Notch1 metabolism, Up-Regulation, Mitral Valve metabolism, Morphogenesis, Receptor, Notch1 genetics, Signal Transduction
Abstract

Rationale: The Notch signaling pathway is crucial for primitive cardiac valve formation by epithelial-mesenchymal transition, and NOTCH1 mutations cause bicuspid aortic valve; however, the temporal requirement for the various Notch ligands and receptors during valve ontogeny is poorly understood., Objective: The aim of this study is to determine the functional specificity of Notch in valve development., Methods and Results: Using cardiac-specific conditional targeted mutant mice, we find that endothelial/endocardial deletion of Mib1-Dll4-Notch1 signaling, possibly favored by Manic-Fringe, is specifically required for cardiac epithelial-mesenchymal transition. Mice lacking endocardial Jag1, Notch1, or RBPJ displayed enlarged valve cusps, bicuspid aortic valve, and septal defects, indicating that endocardial Jag1 to Notch1 signaling is required for post-epithelial-mesenchymal transition valvulogenesis. Valve dysmorphology was associated with increased mesenchyme proliferation, indicating that Jag1-Notch1 signaling restricts mesenchyme cell proliferation non-cell autonomously. Gene profiling revealed upregulated Bmp signaling in Jag1-mutant valves, providing a molecular basis for the hyperproliferative phenotype. Significantly, the negative regulator of mesenchyme proliferation, Hbegf, was markedly reduced in Jag1-mutant valves. Hbegf expression in embryonic endocardial cells could be readily activated through a RBPJ-binding site, identifying Hbegf as an endocardial Notch target. Accordingly, addition of soluble heparin-binding EGF-like growth factor to Jag1-mutant outflow tract explant cultures rescued the hyperproliferative phenotype., Conclusions: During cardiac valve formation, Dll4-Notch1 signaling leads to epithelial-mesenchymal transition and cushion formation. Jag1-Notch1 signaling subsequently restrains Bmp-mediated valve mesenchyme proliferation by sustaining Hbegf-EGF receptor signaling. Our studies identify a mechanism of signaling cross talk during valve morphogenesis involved in the origin of congenital heart defects associated with reduced NOTCH function., (© 2016 American Heart Association, Inc.)

Published
2016
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5. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

Author

Vennin, C, Chin, VT, Warren, SC, Lucas, MC, Herrmann, D, Magenau, A, Melenec, P, Walters, SN, Del Monte-Nieto, G, Conway, JRW, Nobis, M, Allam, AH, McCloy, RA, Currey, N, Pinese, M, Boulghourjian, A, Zaratzian, A, Adam, AAS, Heu, C, Nagrial, AM, Chou, A, Steinmann, A, Drury, A, Froio, D, Giry-Laterriere, M, Harris, NLE, Phan, T, Jain, R, Weninger, W, McGhee, EJ, Whan, R, Johns, AL, Samra, JS, Chantrill, L, Gill, AJ, Kohonen-Corish, M, Harvey, RP, Biankin, AV, Australian Pancreatic Cancer Genome Initiative (APGI), Evans, TRJ, Anderson, KI, Grey, ST, Ormandy, CJ, Gallego-Ortega, D, Wang, Y, Samuel, MS, Sansom, OJ, Burgess, A, Cox, TR, Morton, JP, Pajic, M, and Timpson, P

Subjects
rho-Associated Kinases, Antineoplastic Agents, Biosensing Techniques, Deoxycytidine, Extracellular Matrix, Pancreatic Neoplasms, Actin Cytoskeleton, Mice, Treatment Outcome, src-Family Kinases, Liver, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Cell Line, Tumor, CDC2 Protein Kinase, 06 Biological Sciences, 11 Medical and Health Sciences, Disease Progression, Animals, Humans, Neoplasm Invasiveness, Collagen, Albumin-Bound Paclitaxel, Neoplasm Metastasis, Protein Kinase Inhibitors, Cell Proliferation, Signal Transduction
Abstract

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.

Published
2017

6. Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation

Author

Sarah K. Harten, Alla Aharonov, Gabriele D'Uva, Weinian Shou, Gonzalo del Monte-Nieto, José Luis de la Pompa, Ralf H. Adams, Arne A. S. Adam, Hanying Chen, Richard P. Harvey, Lauren M. Bourke, Bingruo Wu, Eldad Tzahor, Mirana Ramialison, Bin Zhou, Mara E. Pitulescu, del Monte-Nieto G., Ramialison M., Adam A.A.S., Wu B., Aharonov A., D'uva G., Bourke L.M., Pitulescu M.E., Chen H., de la Pompa J.L., Shou W., Adams R.H., Harten S.K., Tzahor E., Zhou B., and Harvey R.P.

Subjects
0301 basic medicine, Vascular Endothelial Growth Factor A, Heart Diseases, Neuregulin-1, Organogenesis, Morphogenesis, Notch signaling pathway, 030204 cardiovascular system & hematology, Biology, Extracellular matrix, 03 medical and health sciences, Mice, 0302 clinical medicine, Animals, Myocyte, Myocytes, Cardiac, Receptor, Notch1, Zebrafish, Multidisciplinary, Cardiac Jelly, Heart development, Animal, Myocardium, Heart, biology.organism_classification, Cell biology, Extracellular Matrix, Disease Models, Animal, 030104 developmental biology, Heart Disease, Extracellular Matrix Degradation, Endocardium, Signal Transduction
Abstract

In vertebrate hearts, the ventricular trabecular myocardium develops as a sponge-like network of cardiomyocytes that is critical for contraction and conduction, ventricular septation, papillary muscle formation and wall thickening through the process of compaction1. Defective trabeculation leads to embryonic lethality2–4 or non-compaction cardiomyopathy (NCC)5. There are divergent views on when and how trabeculation is initiated in different species. In zebrafish, trabecular cardiomyocytes extrude from compact myocardium6, whereas in chicks, chamber wall thickening occurs before overt trabeculation7. In mice, the onset of trabeculation has not been described, but is proposed to begin at embryonic day 9.0, when cardiomyocytes form radially oriented ribs2. Endocardium–myocardium communication is essential for trabeculation, and numerous signalling pathways have been identified, including Notch2,8 and Neuregulin (NRG)4. Late disruption of the Notch pathway causes NCC5. Whereas it has been shown that mutations in the extracellular matrix (ECM) genes Has2 and Vcan prevent the formation of trabeculae in mice9,10 and the matrix metalloprotease ADAMTS1 promotes trabecular termination3, the pathways involved in ECM dynamics and the molecular regulation of trabeculation during its early phases remain unexplored. Here we present a model of trabeculation in mice that integrates dynamic endocardial and myocardial cell behaviours and ECM remodelling, and reveal new epistatic relationships between the involved signalling pathways. NOTCH1 signalling promotes ECM degradation during the formation of endocardial projections that are critical for individualization of trabecular units, whereas NRG1 promotes myocardial ECM synthesis, which is necessary for trabecular rearrangement and growth. These systems interconnect through NRG1 control of Vegfa, but act antagonistically to establish trabecular architecture. These insights enabled the prediction of persistent ECM and cardiomyocyte growth in a mouse NCC model, providing new insights into the pathophysiology of congenital heart disease. A new model of cardiac trabeculation in mice is presented in which NOTCH1 and NRG1 have opposing roles in extracellular matrix degradation and synthesis that are essential for defining trabecular architecture.

Published
2018

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