Imperial College London


Faculty of MedicineNational Heart & Lung Institute




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Publication Type

9 results found

Munshaw S, Bruche S, Redpath AN, Jones A, Patel J, Dubé KN, Lee R, Hester SS, Davies R, Neal G, Handa A, Sattler M, Fischer R, Channon KM, Smart Net al., 2021, Thymosin β4 protects against aortic aneurysm via endocytic regulation of growth factor signaling., J Clin Invest, Vol: 131

Vascular stability and tone are maintained by contractile smooth muscle cells (VSMCs). However, injury-induced growth factors stimulate a contractile-synthetic phenotypic modulation which increases susceptibility to abdominal aortic aneurysm (AAA). As a regulator of embryonic VSMC differentiation, we hypothesized that Thymosin β4 (Tβ4) may function to maintain healthy vasculature throughout postnatal life. This was supported by the identification of an interaction with low density lipoprotein receptor related protein 1 (LRP1), an endocytic regulator of platelet-derived growth factor BB (PDGF-BB) signaling and VSMC proliferation. LRP1 variants have been implicated by genome-wide association studies with risk of AAA and other arterial diseases. Tβ4-null mice displayed aortic VSMC and elastin defects that phenocopy those of LRP1 mutants, and their compromised vascular integrity predisposed them to Angiotensin II-induced aneurysm formation. Aneurysmal vessels were characterized by enhanced VSMC phenotypic modulation and augmented PDGFR-β signaling. In vitro, enhanced sensitivity to PDGF-BB upon loss of Tβ4 was associated with dysregulated endocytosis, with increased recycling and reduced lysosomal targeting of LRP1-PDGFR-β. Accordingly, the exacerbated aneurysmal phenotype in Tβ4-null mice was rescued upon treatment with the PDGFR-β antagonist Imatinib. Our study identifies Tβ4 as a key regulator of LRP1 for maintaining vascular health, and provides insights into the mechanisms of growth factor-controlled VSMC phenotypic modulation underlying aortic disease progression.

Journal article

Brezovjakova H, Tomlinson C, Mohd Naim N, Swiatlowska P, Erasmus JE, Huveneers S, Gorelik J, Bruche S, Braga VMet al., 2019, Junction Mapper is a novel computer vision tool to decipher cell-cell contact phenotypes., eLife, Vol: 8, Pages: 1-48, ISSN: 2050-084X

Stable cell-cell contacts underpin tissue architecture and organization. Quantification of junctions of mammalian epithelia requires laborious manual measurements that are a major roadblock for mechanistic studies. We designed Junction Mapper as an open access, semi-automated software that defines the status of adhesiveness via the simultaneous measurement of pre-defined parameters at cell-cell contacts. It identifies contacting interfaces and corners with minimal user input and quantifies length, area and intensity of junction markers. Its ability to measure fragmented junctions is unique. Importantly, junctions that considerably deviate from the contiguous staining and straight contact phenotype seen in epithelia are also successfully quantified (i.e. cardiomyocytes or endothelia). Distinct phenotypes of junction disruption can be clearly differentiated among various oncogenes, depletion of actin regulators or stimulation with other agents. Junction Mapper is thus a powerful, unbiased and highly applicable software for profiling cell-cell adhesion phenotypes and facilitate studies on junction dynamics in health and disease.

Journal article

Munshaw S, Bruche S, Patel J, Redpath A, Dubé KN, Davies R, Neal G, Lee R, Handa A, Channon KM, Smart Net al., 2019, Thymosin β4 mediates vascular protection via regulation of Low Density Lipoprotein Related Protein 1 (LRP1)

<jats:title>Abstract</jats:title><jats:p>Vascular stability and tone are maintained by contractile smooth muscle cells (VSMCs). However, injury-induced growth factors stimulate a contractile-synthetic phenotypic switch which promotes atherosclerosis and susceptibility to abdominal aortic aneurysm (AAA). As a regulator of embryonic VSMC differentiation, we hypothesised that Thymosin β4 (Tβ4) may additionally function to maintain healthy vasculature and protect against disease throughout postnatal life. This was supported by identification of an interaction with Low density lipoprotein receptor related protein 1 (LRP1), an endocytic regulator of PDGF-BB signalling and VSMC proliferation. LRP1 variants have been identified by GWAS as major risk loci for AAA and coronary artery disease. Tβ4-null mice display aortic VSMC and elastin defects, phenocopying LRP1 mutants and suggesting compromised vascular integrity. We confirmed predisposition to disease in models of atherosclerosis and AAA. Diseased vessels and plaques were characterised by accelerated contractile-synthetic VSMC switching and augmented PDGFRβ signalling. In vitro, enhanced sensitivity to PDGF-BB, upon loss of Tβ4, coincided with dysregulated endocytosis, leading to increased recycling of LRP1-PDGFRβ and reduced lysosomal targeting. Our study identifies Tβ4 as a key regulator of LRP1 for maintaining vascular health, providing insight which may reveal useful therapeutic targets for modulation of VSMC phenotypic switching and disease progression.</jats:p>

Journal article

Bruche S, Zaccolo M, 2018, FRET-ting about RhoA signalling in heart and vasculature: a new tool in our cardiovascular toolbox, CARDIOVASCULAR RESEARCH, Vol: 114, Pages: E25-E27, ISSN: 0008-6363

Journal article

Braga VMM, McCormack JJ, Bruche S, Ouadda ABD, Ishii H, Lu H, Garcia-Cattaneo A, Chavez-Olortegi C, Lamarche-Vane Net al., 2017, The scaffold protein Ajuba suppresses CdGAP activity in epithelia to maintain stable cell-cell contacts, Scientific Reports, Vol: 7, ISSN: 2045-2322

Levels of active Rac1 at epithelial junctions are partially modulated via interaction with Ajuba, an actin binding and scaffolding protein. Here we demonstrate that Ajuba interacts with the Cdc42 GTPase activating protein CdGAP, a GAP for Rac1 and Cdc42, at cell-cell contacts. CdGAP recruitment to junctions does not require Ajuba; rather Ajuba seems to control CdGAP residence at sites of cell-cell adhesion. CdGAP expression potently perturbs junctions and Ajuba binding inhibits CdGAP activity. Ajuba interacts with Rac1 and CdGAP via distinct domains and can potentially bring them in close proximity at junctions to facilitate activity regulation. Functionally, CdGAP-Ajuba interaction maintains junctional integrity in homeostasis and diseases: (i) gain-of-function CdGAP mutants found in Adams-Oliver Syndrome patients strongly destabilize cell-cell contacts and (ii) CdGAP mRNA levels are inversely correlated with E-cadherin protein expression in different cancers. We present conceptual insights on how Ajuba can integrate CdGAP binding and inactivation with the spatio-temporal regulation of Rac1 activity at junctions. Ajuba poses a novel mechanism due to its ability to bind to CdGAP and Rac1 via distinct domains and influence the activation status of both proteins. This functional interplay may contribute towards conserving the epithelial tissue architecture at steady-state and in different pathologies.

Journal article

Erasmus JC, Bruche S, Pizarro L, Maimari N, Poggioli T, Tomlinson C, Lees J, Zalivina I, Wheeler A, Alberts A, Russo A, Braga VMMet al., 2017, Corrigendum: Defining functional interactions during biogenesis of epithelial junctions, Nature Communications, Vol: 8, Pages: 14195-14195, ISSN: 2041-1723

The original version of this Article ( contained an error in the spelling of the author Tommaso Poggioli, which was incorrectly given as Tommaso Pogglioli. This has now been corrected in both the PDF and HTML versions of the Article.

Journal article

Braga VMM, 2016, Defining functional interactions during biogenesis of epithelial junctions, Nature Communications, Vol: 7, Pages: 1-17, ISSN: 2041-1723

In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell-cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases.

Journal article

Bruche S, Gusset M, Lippold S, Barnett R, Eulenberger K, Junhold J, Driscoll CA, Hofreiter Met al., 2013, A genetically distinct lion (Panthera leo) population from Ethiopia, EUROPEAN JOURNAL OF WILDLIFE RESEARCH, Vol: 59, Pages: 215-225, ISSN: 1612-4642

Journal article

Dawson JC, Bruche S, Spence HJ, Braga VMM, Machesky LMet al., 2012, Mtss1 promotes cell-cell junction assembly and stability through the small GTPase Rac1, PLoS One, Vol: 7, ISSN: 1932-6203

Cell-cell junctions are an integral part of epithelia and are often disrupted in cancer cells during epithelial-to-mesenchymal transition (EMT), which is a main driver of metastatic spread. We show here that Metastasis suppressor-1 (Mtss1; Missing in Metastasis, MIM), a member of the IMD-family of proteins, inhibits cell-cell junction disassembly in wound healing or HGF-induced scatter assays by enhancing cell-cell junction strength. Mtss1 not only makes cells more resistant to cell-cell junction disassembly, but also accelerates the kinetics of adherens junction assembly. Mtss1 drives enhanced junction formation specifically by elevating Rac-GTP. Lastly, we show that Mtss1 depletion reduces recruitment of F-actin at cell-cell junctions. We thus propose that Mtss1 promotes Rac1 activation and actin recruitment driving junction maintenance. We suggest that the observed loss of Mtss1 in cancers may compromise junction stability and thus promote EMT and metastasis.

Journal article

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