Publications by authors named "Simon P Pearce"

11 Publications

  • Page 1 of 1

Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse.

Nat Med 2019 10 7;25(10):1534-1539. Epub 2019 Oct 7.

Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, UK.

Approximately 50% of patients with early-stage non-small-cell lung cancer (NSCLC) who undergo surgery with curative intent will relapse within 5 years. Detection of circulating tumor cells (CTCs) at the time of surgery may represent a tool to identify patients at higher risk of recurrence for whom more frequent monitoring is advised. Here we asked whether CellSearch-detected pulmonary venous CTCs (PV-CTCs) at surgical resection of early-stage NSCLC represent subclones responsible for subsequent disease relapse. PV-CTCs were detected in 48% of 100 patients enrolled into the TRACERx study, were associated with lung-cancer-specific relapse and remained an independent predictor of relapse in multivariate analysis adjusted for tumor stage. In a case study, genomic profiling of single PV-CTCs collected at surgery revealed higher mutation overlap with metastasis detected 10 months later (91%) than with the primary tumor (79%), suggesting that early-disseminating PV-CTCs were responsible for disease relapse. Together, PV-CTC enumeration and genomic profiling highlight the potential of PV-CTCs as early predictors of NSCLC recurrence after surgery. However, the limited sensitivity of PV-CTCs in predicting relapse suggests that further studies using a larger, independent cohort are warranted to confirm and better define the potential clinical utility of PV-CTCs in early-stage NSCLC.
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http://dx.doi.org/10.1038/s41591-019-0593-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986897PMC
October 2019

2-Aminomethylene-5-sulfonylthiazole Inhibitors of Lysyl Oxidase (LOX) and LOXL2 Show Significant Efficacy in Delaying Tumor Growth.

J Med Chem 2020 03 4;63(5):2308-2324. Epub 2019 Sep 4.

Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, United Kingdom.

The lysyl oxidase (LOX) family of extracellular proteins plays a vital role in catalyzing the formation of cross-links in fibrillar elastin and collagens leading to extracellular matrix (ECM) stabilization. These enzymes have also been implicated in tumor progression and metastatic disease and have thus become an attractive therapeutic target for many types of invasive cancers. Following our recently published work on the discovery of aminomethylenethiophenes (AMTs) as potent, orally bioavailable LOX/LOXL2 inhibitors, we report herein the discovery of a series of dual LOX/LOXL2 inhibitors, as well as a subseries of LOXL2-selective inhibitors, bearing an aminomethylenethiazole (AMTz) scaffold. Incorporation of a thiazole core leads to improved potency toward LOXL2 inhibition via an irreversible binding mode of inhibition. SAR studies have enabled the discovery of a predictive 3DQSAR model. Lead AMTz inhibitors exhibit improved pharmacokinetic properties and excellent antitumor efficacy, with significantly reduced tumor growth in a spontaneous breast cancer genetically engineered mouse model.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073924PMC
March 2020

Curvature-Sensitive Kinesin Binding Can Explain Microtubule Ring Formation and Reveals Chaotic Dynamics in a Mathematical Model.

Bull Math Biol 2018 11 28;80(11):3002-3022. Epub 2018 Sep 28.

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Microtubules are filamentous tubular protein polymers which are essential for a range of cellular behaviour, and are generally straight over micron length scales. However, in some gliding assays, where microtubules move over a carpet of molecular motors, individual microtubules can also form tight arcs or rings, even in the absence of crosslinking proteins. Understanding this phenomenon may provide important explanations for similar highly curved microtubules which can be found in nerve cells undergoing neurodegeneration. We propose a model for gliding assays where the kinesins moving the microtubules over the surface induce ring formation through differential binding, substantiated by recent findings that a mutant version of the motor protein kinesin applied in solution is able to lock-in microtubule curvature. For certain parameter regimes, our model predicts that both straight and curved microtubules can exist simultaneously as stable steady states, as has been seen experimentally. Additionally, unsteady solutions are found, where a wave of differential binding propagates down the microtubule as it glides across the surface, which can lead to chaotic motion. Whilst this model explains two-dimensional microtubule behaviour in an experimental gliding assay, it has the potential to be adapted to explain pathological curling in nerve cells.
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http://dx.doi.org/10.1007/s11538-018-0505-4DOI Listing
November 2018

RiceAntherNet: a gene co-expression network for identifying anther and pollen development genes.

Plant J 2017 Dec 22;92(6):1076-1091. Epub 2017 Nov 22.

Division of Plant & Crop Sciences, School of Biosciences, University of Nottingham, Loughborough, UK.

In plants, normal anther and pollen development involves many important biological events and complex molecular regulatory coordination. Understanding gene regulatory relationships during male reproductive development is essential for fundamental biology and crop breeding. In this work, we developed a rice gene co-expression network for anther development (RiceAntherNet) that allows prediction of gene regulatory relationships during pollen development. RiceAntherNet was generated from 57 rice anther tissue microarrays across all developmental stages. The microarray datasets from nine rice male sterile mutants, including msp1-4, ostdl1a, gamyb-2, tip2, udt1-1, tdr, eat1-1, ptc1 and mads3-4, were used to explore and test the network. Among the changed genes, three clades showing differential expression patterns were constructed to identify genes associated with pollen formation. Many of these have known roles in pollen development, for example, seven genes in Clade 1 (OsABCG15, OsLAP5, OsLAP6, DPW, CYP703A3, OsNP1 and OsCP1) are involved in rice pollen wall formation. Furthermore, Clade 1 contained 12 genes whose predicted orthologs in Arabidopsis have been reported as key during pollen development and may play similar roles in rice. Genes in Clade 2 are expressed earlier than Clade 1 (anther stages 2-9), while genes in Clade 3 are expressed later (stages 10-12). RiceAntherNet serves as a valuable tool for identifying novel genes during plant anther and pollen development. A website is provided (https://www.cpib.ac.uk/anther/riceindex.html) to present the expression profiles for gene characterization. This will assist in determining the key relationships between genes, thus enabling characterization of critical genes associated with anther and pollen regulatory networks.
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http://dx.doi.org/10.1111/tpj.13744DOI Listing
December 2017

Periodic actin structures in neuronal axons are required to maintain microtubules.

Mol Biol Cell 2017 01 23;28(2):296-308. Epub 2016 Nov 23.

Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom

Axons are cable-like neuronal processes wiring the nervous system. They contain parallel bundles of microtubules as structural backbones, surrounded by regularly spaced actin rings termed the periodic membrane skeleton (PMS). Despite being an evolutionarily conserved, ubiquitous, highly ordered feature of axons, the function of PMS is unknown. Here we studied PMS abundance, organization, and function, combining versatile Drosophila genetics with superresolution microscopy and various functional readouts. Analyses with 11 actin regulators and three actin-targeting drugs suggest that PMS contains short actin filaments that are depolymerization resistant and sensitive to spectrin, adducin, and nucleator deficiency, consistent with microscopy-derived models proposing PMS as specialized cortical actin. Upon actin removal, we observed gaps in microtubule bundles, reduced microtubule polymerization, and reduced axon numbers, suggesting a role of PMS in microtubule organization. These effects become strongly enhanced when carried out in neurons lacking the microtubule-stabilizing protein Short stop (Shot). Combining the aforementioned actin manipulations with Shot deficiency revealed a close correlation between PMS abundance and microtubule regulation, consistent with a model in which PMS-dependent microtubule polymerization contributes to their maintenance in axons. We discuss potential implications of this novel PMS function along axon shafts for axon maintenance and regeneration.
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http://dx.doi.org/10.1091/mbc.E16-10-0727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5231898PMC
January 2017

A conceptual view at microtubule plus end dynamics in neuronal axons.

Brain Res Bull 2016 09 12;126(Pt 3):226-237. Epub 2016 Aug 12.

The University of Manchester, Faculty of Biology, Medicine and Health, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK. Electronic address:

Axons are the cable-like protrusions of neurons which wire up the nervous system. Polar bundles of microtubules (MTs) constitute their structural backbones and are highways for life-sustaining transport between proximal cell bodies and distal synapses. Any morphogenetic changes of axons during development, plastic rearrangement, regeneration or degeneration depend on dynamic changes of these MT bundles. A key mechanism for implementing such changes is the coordinated polymerisation and depolymerisation at the plus ends of MTs within these bundles. To gain an understanding of how such regulation can be achieved at the cellular level, we provide here an integrated overview of the extensive knowledge we have about the molecular mechanisms regulating MT de/polymerisation. We first summarise insights gained from work in vitro, then describe the machinery which supplies the essential tubulin building blocks, the protein complexes associating with MT plus ends, and MT shaft-based mechanisms that influence plus end dynamics. We briefly summarise the contribution of MT plus end dynamics to important cellular functions in axons, and conclude by discussing the challenges and potential strategies of integrating the existing molecular knowledge into conceptual understanding at the level of axons.
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http://dx.doi.org/10.1016/j.brainresbull.2016.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5090033PMC
September 2016

Dormant and after-Ripened Arabidopsis thaliana Seeds are Distinguished by Early Transcriptional Differences in the Imbibed State.

Front Plant Sci 2016 30;7:1323. Epub 2016 Aug 30.

Wageningen Seed Laboratory, Laboratory of Plant Physiology, Wageningen University Wageningen, Netherlands.

Seed dormancy is a genetically controlled block preventing the germination of imbibed seeds in favorable conditions. It requires a period of dry storage (after-ripening) or certain environmental conditions to be overcome. Dormancy is an important seed trait, which is under selective pressure, to control the seasonal timing of seed germination. Dormant and non-dormant (after-ripened) seeds are characterized by large sets of differentially expressed genes. However, little information is available concerning the temporal and spatial transcriptional changes during early stages of rehydration in dormant and non-dormant seeds. We employed genome-wide transcriptome analysis on seeds of the model plant Arabidopsis thaliana to investigate transcriptional changes in dry seeds upon rehydration. We analyzed gene expression of dormant and after-ripened seeds of the Cvi accession over four time points and two seed compartments (the embryo and surrounding single cell layer endosperm), during the first 24 h after sowing. This work provides a global view of gene expression changes in dormant and non-dormant seeds with temporal and spatial detail, and these may be visualized via a web accessible tool (http://www.wageningenseedlab.nl/resources). A large proportion of transcripts change similarly in both dormant and non-dormant seeds upon rehydration, however, the first differences in transcript abundances become visible shortly after the initiation of imbibition, indicating that changes induced by after-ripening are detected and responded to rapidly upon rehydration. We identified several gene expression profiles which contribute to differential gene expression between dormant and non-dormant samples. Genes with enhanced expression in the endosperm of dormant seeds were overrepresented for stress-related Gene Ontology categories, suggesting a protective role for the endosperm against biotic and abiotic stress to support persistence of the dormant seed in its environment.
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http://dx.doi.org/10.3389/fpls.2016.01323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003841PMC
September 2016

Promotion of testa rupture during garden cress germination involves seed compartment-specific expression and activity of pectin methylesterases.

Plant Physiol 2015 Jan 26;167(1):200-15. Epub 2014 Nov 26.

Botany and Plant Physiology, Institute for Biology II, Faculty of Biology, University of Freiburg, D-79104 Freiburg, Germany (C.S., K.W., A.B.-M., K.O., G.L.-M.);Institute of Biochemical Plant Pathology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, D-85764 Neuherberg, Germany (C.S.);Staatliches Weinbauinstitut Freiburg, D-79104 Freiburg, Germany (K.W.);Centre for Plant Integrative Biology (S.P.P., A.H., A.T.A.W., J.R.K., M.J.H.) and Division of Plant and Crop Science (S.P.P., M.J.H., K.M.), School of Biosciences, University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire LE12 5RD, United Kingdom;School of Mathematical Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom (S.P.P., A.H., A.T.A.W., J.R.K.)Agroscope, Institute for Plant Production Sciences, Seed Quality, CH-8046 Zurich, Switzerland (A.B.-M.);Centre for Plant Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom (K.J.D.L., J.P.K.);National Institute for Health Research Trainees Coordinating Centre, Leeds Innovation Centre, Leeds LS2 9DF, United Kingdom (K.J.D.L.);School of Biological Sciences, Plant Molecular Science and Centre for Systems and Synthetic Biology, Royal Holloway, University of London, Egham, Surrey TW20 0EX, United Kingdom (A.V., G.L.-M.);Department of Plant Physiology, Warsaw University of Life Sciences, 02-776, Warsaw, Poland (K.O.);Wageningen Seed Laboratory, Laboratory of Plant Physiology, Wageningen University and Research Centre, NL-6708 PB Wageningen, The Netherlands (B.J.W.D., L.B.);College of Life Sciences, South China Agricultural University, Guangzhou 510642, China (X.W.); andLaboratory of Growth Regulators, Faculty of Science, Palacký University and Institute of Experimental Botany, CZ-783 71 Olomouc, Czech Republic (G.L.-M.)

Pectin methylesterase (PME) controls the methylesterification status of pectins and thereby determines the biophysical properties of plant cell walls, which are important for tissue growth and weakening processes. We demonstrate here that tissue-specific and spatiotemporal alterations in cell wall pectin methylesterification occur during the germination of garden cress (Lepidium sativum). These cell wall changes are associated with characteristic expression patterns of PME genes and resultant enzyme activities in the key seed compartments CAP (micropylar endosperm) and RAD (radicle plus lower hypocotyl). Transcriptome and quantitative real-time reverse transcription-polymerase chain reaction analysis as well as PME enzyme activity measurements of separated seed compartments, including CAP and RAD, revealed distinct phases during germination. These were associated with hormonal and compartment-specific regulation of PME group 1, PME group 2, and PME inhibitor transcript expression and total PME activity. The regulatory patterns indicated a role for PME activity in testa rupture (TR). Consistent with a role for cell wall pectin methylesterification in TR, treatment of seeds with PME resulted in enhanced testa permeability and promoted TR. Mathematical modeling of transcript expression changes in germinating garden cress and Arabidopsis (Arabidopsis thaliana) seeds suggested that group 2 PMEs make a major contribution to the overall PME activity rather than acting as PME inhibitors. It is concluded that regulated changes in the degree of pectin methylesterification through CAP- and RAD-specific PME and PME inhibitor expression play a crucial role during Brassicaceae seed germination.
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http://dx.doi.org/10.1104/pp.114.247429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280999PMC
January 2015

Systems analysis of auxin transport in the Arabidopsis root apex.

Plant Cell 2014 Mar 14;26(3):862-75. Epub 2014 Mar 14.

Centre for Plant Integrative Biology, University of Nottingham, Nottingham LE12 5RD, United Kingdom.

Auxin is a key regulator of plant growth and development. Within the root tip, auxin distribution plays a crucial role specifying developmental zones and coordinating tropic responses. Determining how the organ-scale auxin pattern is regulated at the cellular scale is essential to understanding how these processes are controlled. In this study, we developed an auxin transport model based on actual root cell geometries and carrier subcellular localizations. We tested model predictions using the DII-VENUS auxin sensor in conjunction with state-of-the-art segmentation tools. Our study revealed that auxin efflux carriers alone cannot create the pattern of auxin distribution at the root tip and that AUX1/LAX influx carriers are also required. We observed that AUX1 in lateral root cap (LRC) and elongating epidermal cells greatly enhance auxin's shootward flux, with this flux being predominantly through the LRC, entering the epidermal cells only as they enter the elongation zone. We conclude that the nonpolar AUX1/LAX influx carriers control which tissues have high auxin levels, whereas the polar PIN carriers control the direction of auxin transport within these tissues.
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http://dx.doi.org/10.1105/tpc.113.119495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001398PMC
March 2014

Nitric oxide sensing in plants is mediated by proteolytic control of group VII ERF transcription factors.

Mol Cell 2014 Feb 23;53(3):369-79. Epub 2014 Jan 23.

Division of Plant and Crop Sciences, School of Biosciences, University of Nottingham, Loughborough LE12 5RD, UK. Electronic address:

Nitric oxide (NO) is an important signaling compound in prokaryotes and eukaryotes. In plants, NO regulates critical developmental transitions and stress responses. Here, we identify a mechanism for NO sensing that coordinates responses throughout development based on targeted degradation of plant-specific transcriptional regulators, the group VII ethylene response factors (ERFs). We show that the N-end rule pathway of targeted proteolysis targets these proteins for destruction in the presence of NO, and we establish them as critical regulators of diverse NO-regulated processes, including seed germination, stomatal closure, and hypocotyl elongation. Furthermore, we define the molecular mechanism for NO control of germination and crosstalk with abscisic acid (ABA) signaling through ERF-regulated expression of ABSCISIC ACID INSENSITIVE5 (ABI5). Our work demonstrates how NO sensing is integrated across multiple physiological processes by direct modulation of transcription factor stability and identifies group VII ERFs as central hubs for the perception of gaseous signals in plants.
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http://dx.doi.org/10.1016/j.molcel.2013.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969242PMC
February 2014