Cristina Bertocchi
Email Address
mbicb@nus.edu.sg
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Publication Junctional ER Organization Affects Mechanotransduction at Cadherin-Mediated Adhesions(Frontiers Media SA, 2021-06) Joy-Immediato, Michelle; Ramirez, Manuel J; Cerda, Mauricio; Toyama, Yusuke; Ravasio, Andrea; Kanchanawong, Pakorn; Bertocchi, Cristina; Assoc Prof Pakorn Kanchanawong; BIOMEDICAL ENGINEERING; MECHANOBIOLOGY INSTITUTE; BIOLOGICAL SCIENCESCadherin-mediated adhesions (also known as adherens junctions) are adhesive complexes that connect neighboring cells in a tissue. While the role of the actin cytoskeleton in withstanding tension at these sites of contact is well documented, little is known about the involvement of microtubules and the associated endoplasmic reticulum (ER) network in cadherin mechanotransduction. Therefore, we investigated how the organization of ER extensions in close proximity of cadherin-mediated adhesions can affect such complexes, and vice versa. Here, we show that the extension of the ER to cadherin-mediated adhesions is tension dependent and appears to be cadherin-type specific. Furthermore, the different structural organization of the ER/microtubule network seems to affect the localization of ER-bound PTP1B at cadherin-mediated adhesions. This phosphatase is involved in the modulation of vinculin, a molecular clutch which enables differential engagement of the cadherin-catenin layer with the actomyosin cytoskeleton in response to tension. This suggests a link between structural organization of the ER/microtubule network around cadherin-specific adhesions, to control the mechanotransduction of adherens junctions by modulation of vinculin conformational state.Publication Nanoscale architecture of cadherin-based cell adhesions(NATURE PUBLISHING GROUP, 2017-01-01) Bertocchi, Cristina; Wang, Yilin; Ravasio, Andrea; Hara, Yusuke; Wu, Yao; Sailov, Talgat; Baird, Michelle A; Davidson, Michael W; Zaidel-Bar, Ronen; Toyama, Yusuke; Ladoux, Benoit; Mege, Rene-Marc; Kanchanawong, Pakorn; Assoc Prof Pakorn Kanchanawong; BIOMEDICAL ENGINEERING; MECHANOBIOLOGY INSTITUTE; BIOLOGICAL SCIENCESMulticellularity in animals requires dynamic maintenance of cell-cell contacts. Intercellularly ligated cadherins recruit numerous proteins to form supramolecular complexes that connect with the actin cytoskeleton and support force transmission. However, the molecular organization within such structures remains unknown. Here we mapped protein organization in cadherin-based adhesions by super-resolution microscopy, revealing a multi-compartment nanoscale architecture, with the plasma-membrane-proximal cadherin-catenin compartment segregated from the actin cytoskeletal compartment, bridged by an interface zone containing vinculin. Vinculin position is determined by α-catenin, and following activation, vinculin can extend â 1/430 nm to bridge the cadherin-catenin and actin compartments, while modulating the nanoscale positions of the actin regulators zyxin and VASP. Vinculin conformational activation requires tension and tyrosine phosphorylation, regulated by Abl kinase and PTP1B phosphatase. Such modular architecture provides a structural framework for mechanical and biochemical signal integration by vinculin, which may differentially engage cadherin-catenin complexes with the actomyosin machinery to regulate cell adhesions.Publication Author Correction: Single-cell analysis of EphA clustering phenotypes to probe cancer cell heterogeneity (Communications biology (2020) 3 1 (429))(NLM (Medline), 2020) Ravasio, A.; Myaing, M.Z.; Chia, S.; Arora, A.; Sathe, A.; Cao, E.Y.; Bertocchi, Cristina; Sharma, A.; Arasi, B.; Chung, V.Y.; Green, A.C.; Tan, T.Z.; Chen, Z.; Ong, H.T.; Iyer, N.G.; Huang, R.Y.; DasGupta, R.; Groves, J.T.; Viasnoff, V.; MECHANOBIOLOGY INSTITUTE; CANCER SCIENCE INSTITUTE OF SINGAPORE; BIOLOGICAL SCIENCES; DUKE-NUS MEDICAL SCHOOL; OBSTETRICS & GYNAECOLOGYAn amendment to this paper has been published and can be accessed via a link at the top of the paper.Publication Levosimendan inhibits release of reactive oxygen species in polymorphonuclear leukocytes in vitro and in patients with acute heart failure and septic shock: A prospective observational study(2011) Hasslacher, J; Bijuklic, K; Bertocchi, C; Kountchev, J; Bellmann, R; Dunzendorfer, S; Joannidis, M; MECHANOBIOLOGY INSTITUTEIntroduction: Levosimendan is an extensively investigated inodilator showing also cardioprotective and antiinflammatory effects. The aim of our study was to explore the influence of levosimendan on polymorphonuclear leucocytes (PMN), a main source of reactive oxygen species, in vitro and in patients with acute heart failure or septic myocardial depression.Methods: PMN isolated from healthy volunteers were incubated with levosimendan in vitro. After stimulation with N-formyl-Met-Leu-Phe (fMLP) or phorbol 12-myristate 13-acetate (PMA) respiratory burst was quantified using a fluorescent dye. Apoptosis and expression of cell adhesion molecules of PMN were measured by flow cytometry. For determination of in vivo effects patients with acute heart failure (n = 16) or septic cardiac failure (n = 9) receiving levosimendan treatment were enrolled consecutively. PMN were isolated to measure respiratory burst activity before treatment as well as one and two hours after initiation of levosimendan administration. Furthermore inflammatory, hemodynamic and renal function parameters were obtained.Results: In vitro, levosimendan suppressed respiratory burst activity in fMLP or PMA stimulated PMN in a dose dependent manner by 30 ± 11% (P < 0.001) at 100 ng/mL and by 27 ± 17% (P < 0.001) at 1000 ng/mL respectively. Markers of apoptosis and PMN cell adhesion molecule expression remained unaffected by levosimendan treatment.In vivo, levosimendan treatment for two hours resulted in a significant reduction of PMA stimulated oxidative burst by 45% (P < 0.01) and fMLP stimulated oxidative burst by 49% (P < 0.05) in patients with acute heart failure. In patients suffering from septic shock levosimendan treatment decreased oxidative burst activity in unstimulated, fMLP and PMA stimulated PMN by 48% (P < 0.05), 46% (P < 0.01) and 43% (P < 0.01) respectively.Conclusions: Levosimendan appears to exert distinct immunomodulatory effects by decreasing oxidative burst activity of PMN. This property might contribute to the previously described cardioprotective effects of the drug. © 2011 Hasslacher et al.; licensee BioMed Central Ltd.Publication Author Correction: Single-cell analysis of EphA clustering phenotypes to probe cancer cell heterogeneity(NATURE RESEARCH, 2020-11-06) Ravasio, Andrea; Myaing, Myint Z; Chia, Shumei; Arora, Aditya; Sathe, Aneesh; Cao, Elaine Yiqun; Bertocchi, Cristina; Sharma, Ankur; Arasi, Bakya; Chung, Vin Yee; Greene, Adrienne C; Tan, Tuan Zea; Chen, Zhongwen; Ong, Hui Ting; Iyer, N Gopalakrishna; Huang, Ruby YunJu; DasGupta, Ramanuj; Groves, Jay T; Viasnoff, Virgile; Assoc Prof Virgile Nicolas Robert Viasnoff; MECHANOBIOLOGY INSTITUTE; CANCER SCIENCE INSTITUTE OF SINGAPORE; DUKE-NUS MEDICAL SCHOOLAn amendment to this paper has been published and can be accessed via a link at the top of the paper.Publication Single-cell analysis of EphA clustering phenotypes to probe cancer cell heterogeneity(Nature Research, 2020-08-06) Ravasio, Andrea; Myaing, Myint Z; Chia, Shumei; Arora, Aditya; Sathe, Aneesh; Cao, Elaine Yiqun; Bertocchi, Cristina; Sharma, Ankur; Arasi, Bakya; Chung, Vin Yee; Greene, Adrienne C; Tan, Tuan Zea; Chen, Zhongwen; Ong, Hui Ting; Iyer, N Gopalakrishna; Huang, Ruby YunJu; DasGupta, Ramanuj; Groves, Jay T; Viasnoff, Virgile; MECHANOBIOLOGY INSTITUTE; CANCER SCIENCE INSTITUTE OF SINGAPORE; DUKE-NUS MEDICAL SCHOOLThe Eph family of receptor tyrosine kinases is crucial for assembly and maintenance of healthy tissues. Dysfunction in Eph signaling is causally associated with cancer progression. In breast cancer cells, dysregulated Eph signaling has been linked to alterations in receptor clustering abilities. Here, we implemented a single-cell assay and a scoring scheme to systematically probe the spatial organization of activated EphA receptors in multiple carcinoma cells. We show that cancer cells retain EphA clustering phenotype over several generations, and the degree of clustering reported for migration potential both at population and single-cell levels. Finally, using patient-derived cancer lines, we probed the evolution of EphA signalling in cell populations that underwent metastatic transformation and acquisition of drug resistance. Taken together, our scalable approach provides a reliable scoring scheme for EphA clustering that is consistent over multiple carcinomas and can assay heterogeneity of cancer cell populations in a cost- and time-effective manner. @ 2020, The Author(s).Publication Gap geometry dictates epithelial closure efficiency(Nature Publishing Group, 2015) Ravasio, A; Cheddadi, I; Chen, T; Pereira, T; Ong, H.T; Bertocchi, C; Brugues, A; Jacinto, A; Kabla, A.J; Toyama, Y; Trepat, X; Gov, N; Neves De Almeida, L; Ladoux, B; BIOLOGY; MECHANOBIOLOGY INSTITUTE; BIOLOGICAL SCIENCESClosure of wounds and gaps in tissues is fundamental for the correct development and physiology of multicellular organisms and, when misregulated, may lead to inflammation and tumorigenesis. To re-establish tissue integrity, epithelial cells exhibit coordinated motion into the void by active crawling on the substrate and by constricting a supracellular actomyosin cable. Coexistence of these two mechanisms strongly depends on the environment. However, the nature of their coupling remains elusive because of the complexity of the overall process. Here we demonstrate that epithelial gap geometry in both in vitro and in vivo regulates these collective mechanisms. In addition, the mechanical coupling between actomyosin cable contraction and cell crawling acts as a large-scale regulator to control the dynamics of gap closure. Finally, our computational modelling clarifies the respective roles of the two mechanisms during this process, providing a robust and universal mechanism to explain how epithelial tissues restore their integrity. © 2015 Macmillan Publishers Limited. All rights reserved.