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2 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. A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts.

Author

Nobis M, Herrmann D, Warren SC, Kadir S, Leung W, Killen M, Magenau A, Stevenson D, Lucas MC, Reischmann N, Vennin C, Conway JRW, Boulghourjian A, Zaratzian A, Law AM, Gallego-Ortega D, Ormandy CJ, Walters SN, Grey ST, Bailey J, Chtanova T, Quinn JMW, Baldock PA, Croucher PI, Schwarz JP, Mrowinska A, Zhang L, Herzog H, Masedunskas A, Hardeman EC, Gunning PW, Del Monte-Nieto G, Harvey RP, Samuel MS, Pajic M, McGhee EJ, Johnsson AE, Sansom OJ, Welch HCE, Morton JP, Strathdee D, Anderson KI, and Timpson P

Subjects
Animals, Antineoplastic Agents pharmacology, Bone and Bones cytology, Bone and Bones metabolism, Cell Movement drug effects, Dasatinib pharmacology, Erlotinib Hydrochloride pharmacology, Female, Fluorescence Resonance Energy Transfer instrumentation, Gene Expression Regulation, Intestine, Small metabolism, Intestine, Small ultrastructure, Intravital Microscopy instrumentation, Mammary Glands, Animal blood supply, Mammary Glands, Animal drug effects, Mammary Glands, Animal ultrastructure, Mammary Neoplasms, Experimental blood supply, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental genetics, Mammary Neoplasms, Experimental ultrastructure, Mechanotransduction, Cellular, Mice, Mice, Transgenic, Neutrophils metabolism, Neutrophils ultrastructure, Osteocytes metabolism, Osteocytes ultrastructure, Pancreatic Neoplasms blood supply, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms ultrastructure, Time-Lapse Imaging instrumentation, rho GTP-Binding Proteins metabolism, rhoA GTP-Binding Protein, Biosensing Techniques, Fluorescence Resonance Energy Transfer methods, Intravital Microscopy methods, Time-Lapse Imaging methods, rho GTP-Binding Proteins genetics
Abstract

The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2017
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