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PtdIns(3,4,5)P-dependent Rac exchanger 1 (P-Rex1) promotes mammary tumor initiation and metastasis.
Srijakotre N, Liu HJ, Nobis M, Man J, Yip HYK, Papa A, Abud HE, Anderson KI, Welch HCE, Tiganis T, Timpson P, McLean CA, Ooms LM, Mitchell CA
The Rac-GEF, P-Rex1, activates Rac1 signaling downstream of G protein-coupled receptors and PI3K. Increased P-Rex1 expression promotes melanoma progression; however, its role in breast cancer is complex, with differing reports of the effect of its expression on disease outcome. To address this we analyzed human databases, undertook gene array expression analysis, and generated unique murine models of P-Rex1 gain or loss of function. Analysis of mRNA expression in breast cancer cDNA arrays and a METABRIC cohort revealed that higher mRNA in ER/luminal tumors was associated with poor outcome in luminal B cancers. deletion in MMTV- or MMTV- mice reduced Rac1 activation in vivo and improved survival. High level MMTVdriven transgenic expression resulted in apicobasal polarity defects and increased mammary epithelial cell proliferation associated with hyperplasia and development of de novo mammary tumors. MMTV- expression in MMTV- mice increased tumor initiation and enhanced metastasis in vivo, but had no effect on primary tumor growth. Pharmacological inhibition of Rac1 or MEK1/2 reduced P-Rex1-driven tumoroid formation and cell invasion. Therefore, P-Rex1 can act as an oncogene and cooperate with HER2/neu to enhance breast cancer initiation and metastasis, despite having no effect on primary tumor growth.
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Proceedings of the National Academy of Sciences of the United States of America,
1,
1,
23 Oct 2020
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Removing physiological motion from intravital and clinical functional imaging data.
Warren SC, Nobis M, Magenau A, Mohammed YH, Herrmann D, Moran I, Vennin C, Conway JR, Mélénec P, Cox TR, Wang Y, Morton JP, Welch HC, Strathdee D, Anderson KI, Phan TG, Roberts MS, Timpson P
Intravital microscopy can provide unique insights into the function of biological processes in a native context. However, physiological motion caused by peristalsis, respiration and the heartbeat can present a significant challenge, particularly for functional readouts such as fluorescence lifetime imaging (FLIM), which require longer acquisition times to obtain a quantitative readout. Here, we present and benchmark , a versatile multi-platform software tool for image-based correction of sample motion blurring in both time resolved and conventional laser scanning fluorescence microscopy data in two and three dimensions. We show that is able to resolve intravital FLIM-FRET images of intra-abdominal organs in murine models and NADH autofluorescence of human dermal tissue imaging subject to a wide range of physiological motions. Thus, can enable FLIM imaging in situations where a stable imaging platform is not always possible and rescue previously discarded quantitative imaging data.
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eLife,
7,
2050-084X,
2018
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Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment.
Pantarelli C, Welch HCE
Rac-GTPases and their Rac-GEF activators play important roles in the recruitment and host defense functions of neutrophils. These proteins control the activation of adhesion molecules and the cytoskeletal dynamics that enable the adhesion, migration and tissue recruitment of neutrophils. They also regulate the effector functions that allow neutrophils to kill bacterial and fungal pathogens, and to clear debris. This review focusses on the roles of Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment. This article is protected by copyright. All rights reserved.
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European journal of clinical investigation,
,
1365-2362,
2018
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