海角社区论坛

Simon Walker

Simon Walker
Simon Walker
Simon Walker
Head of Imaging Facility
Simon Walker

Simon has a BSc in Biochemistry from Hertiot-Watt University (Edinburgh) and a PhD from the University of East Anglia (Norwich). Simon studied for his PhD at the John Innes Centre in Norwich under the supervision of Prof. J. Allan Downie, investigating the role of calcium signalling during legume symbiosis. It was during this time that Simon first used a confocal microscope, sparking an interest in microscopy and imaging technology.

Following his PhD, Simon went to work as a postdoc in Pete Cullen's lab in the Department of Biochemistry at Bristol University, investigating Ras GTPase-activating proteins. These studies required the use of various microscopy systems and cemented Simon鈥檚 passion for biological imaging. Simon moved to the 海角社区论坛 in 2004 where he established the Institute鈥檚 core Imaging Facility.

The Imaging Facility now provides state-of-the-art microscopy services essential for the delivery of Institute science and is an important Babraham Research Campus resource supporting the commercial research community.

Latest Publications

Open Access
Collins DM, Janardan V, Barneda D, Anderson KE, Niewczas I, Taylor D, Qiu D, Jessen HJ, Lopez-Clavijo AF, Walker S, Raghu P, Clark J, Stephens LR, Hawkins PT Signalling , Imaging , Lipidomics , Biological Chemistry

CDS enzymes (CDS1 and 2 in mammals) convert phosphatidic acid (PA) to CDP-DG, an essential intermediate in the de novo synthesis of PI. Genetic deletion of CDS2 in primary mouse macrophages resulted in only modest changes in the steady-state levels of major phospholipid species, including PI, but substantial increases in several species of PA, CDP-DG, DG and TG. Stable isotope labelling experiments employing both 13C6- and 13C6D7-glucose revealed loss of CDS2 resulted in a minimal reduction in the rate of de novo PI synthesis but a substantial increase in the rate of de novo PA synthesis from G3P, derived from DHAP via glycolysis. This increased synthesis of PA provides a potential explanation for normal basal PI synthesis in the face of reduced CDS capacity (via increased provision of substrate to CDS1) and increased synthesis of DG and TG (via increased provision of substrate to LIPINs). However, under conditions of sustained GPCR-stimulation of PLC, CDS2-deficient macrophages were unable to maintain enhanced rates of PI synthesis via the 'PI cycle', leading to a substantial loss of PI. CDS2-deficient macrophages also exhibited significant defects in calcium homeostasis which were unrelated to the activation of PLC and thus probably an indirect effect of increased basal PA. These experiments reveal that an important homeostatic response in mammalian cells to a reduction in CDS capacity is increased de novo synthesis of PA, likely related to maintaining normal levels of PI, and provides a new interpretation of previous work describing pleiotropic effects of CDS2 deletion on lipid metabolism/signalling.

+view abstract The Biochemical journal, PMID: 39312194

Picco G, Rao Y, Al Saedi A, Lee Y, Vieira SF, Bhosle S, May K, Herranz-Ors C, Walker SJ, Shenje R, Dincer C, Gibson F, Banerjee R, Hewitson Z, Werner T, Cottom JE, Peng Y, Deng N, Zhang Y, Nartey EN, Nickels L, Landis P, Conticelli D, McCarten K, Bush J, Sharma M, Lightfoot H, House D, Milford E, Grant EK, Glogowski MP, Wagner CD, Bantscheff M, Rutkowska-Klute A, , Zappacosta F, Pettinger J, Barthorpe S, Eberl HC, Jones BT, Schneck JL, Murphy DJ, Voest EE, Taygerly JP, DeMartino MP, Coelho MA, Houseley J, Sharma G, Schwartz B, Garnett MJ Epigenetics

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth in vitro and in vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic lethal targeting of WRN in MSI cancer and tools to dissect WRN biology. Significance: We report the discovery and characterization of potent, selective WRN helicase inhibitors for MSI cancer treatment, with biomarker analysis and evaluation of efficacy in vivo and in immunotherapy-refractory preclinical models. These findings pave the way to translate WRN inhibition into MSI cancer therapies and provide tools to investigate WRN biology. See related commentary by Wainberg, p. 1369.

+view abstract Cancer discovery, PMID: 38587317

Open Access
Hornigold K, Baker MJ, Machin PA, Chetwynd SA, Johnsson AK, Pantarelli C, Islam P, Stammers M, Crossland L, Oxley D, Okkenhaug H, Walker S, Walker R, Segonds-Pichon A, Fukui Y, Malliri A, Welch HCE Signalling , Imaging , Mass Spectrometry , Bioinformatics , Flow Cytometry

Rac GTPases are required for neutrophil adhesion and migration, and for the neutrophil effector responses that kill pathogens. These Rac-dependent functions are impaired when neutrophils lack the activators of Rac, Rac-GEFs from the Prex, Vav, and Dock families. In this study, we demonstrate that Tiam1 is also expressed in neutrophils, governing focal complexes, actin cytoskeletal dynamics, polarisation, and migration, in a manner depending on the integrin ligand to which the cells adhere. Tiam1 is dispensable for the generation of reactive oxygen species but mediates degranulation and NETs release in adherent neutrophils, as well as the killing of bacteria. , Tiam1 is required for neutrophil recruitment during aseptic peritonitis and for the clearance of during pulmonary infection. However, Tiam1 functions differently to other Rac-GEFs. Instead of promoting neutrophil adhesion to ICAM1 and stimulating 尾2 integrin activity as could be expected, Tiam1 restricts these processes. In accordance with these paradoxical inhibitory roles, Tiam1 limits the fMLP-stimulated activation of Rac1 and Rac2 in adherent neutrophils, rather than activating Rac as expected. Tiam1 promotes the expression of several regulators of small GTPases and cytoskeletal dynamics, including 伪Pix, Psd4, Rasa3, and Tiam2. It also controls the association of Rasa3, and potentially 伪Pix, Git2, Psd4, and 14-3-3味/未, with Rac. We propose these latter roles of Tiam1 underlie its effects on Rac and 尾2 integrin activity and on cell responses. Hence, Tiam1 is a novel regulator of Rac-dependent neutrophil responses that functions differently to other known neutrophil Rac-GEFs.

+view abstract Frontiers in immunology, PMID: 38077328

Group Members

Simon Walker

Head of Imaging Facility

Kirsty MacLellan-Gibson

Deputy Facility Manager & Senior EM Specialist

Hanneke Okkenhaug

Imaging Facility Deputy Manager

Isabel San Martin Molina

Imaging Specialist