17 results on '"Castillo, Sandra D."'
Search Results
2. p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response
- Author
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Serra, François, Nieto-Aliseda, Andrea, Fanlo-Escudero, Lucía, Rovirosa, Llorenç, Cabrera-Pasadas, Mónica, Lazarenkov, Aleksey, Urmeneta, Blanca, Alcalde-Merino, Alvaro, Nola, Emanuele M., Okorokov, Andrei L., Fraser, Peter, Graupera, Mariona, Castillo, Sandra D., Sardina, Jose L., Valencia, Alfonso, and Javierre, Biola M.
- Published
- 2024
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3. Behavioural immune landscapes of inflammation
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Crainiciuc, Georgiana, Palomino-Segura, Miguel, Molina-Moreno, Miguel, Sicilia, Jon, Aragones, David G., Li, Jackson Liang Yao, Madurga, Rodrigo, Adrover, José M., Aroca-Crevillén, Alejandra, Martin-Salamanca, Sandra, del Valle, Alfonso Serrano, Castillo, Sandra D., Welch, Heidi C. E., Soehnlein, Oliver, Graupera, Mariona, Sánchez-Cabo, Fátima, Zarbock, Alexander, Smithgall, Thomas E., Di Pilato, Mauro, Mempel, Thorsten R., Tharaux, Pierre-Louis, González, Santiago F., Ayuso-Sacido, Angel, Ng, Lai Guan, Calvo, Gabriel F., González-Díaz, Iván, Díaz-de-María, Fernando, and Hidalgo, Andrés
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- 2022
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4. The onset of PI3K‐related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib
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Kobialka, Piotr, Sabata, Helena, Vilalta, Odena, Gouveia, Leonor, Angulo‐Urarte, Ana, Muixí, Laia, Zanoncello, Jasmina, Muñoz‐Aznar, Oscar, Olaciregui, Nagore G, Fanlo, Lucia, Esteve‐Codina, Anna, Lavarino, Cinzia, Javierre, Biola M, Celis, Veronica, Rovira, Carlota, López‐Fernández, Susana, Baselga, Eulàlia, Mora, Jaume, Castillo, Sandra D, and Graupera, Mariona
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- 2022
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5. Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation
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Martinez-Corral, Ines, Zhang, Yan, Petkova, Milena, Ortsäter, Henrik, Sjöberg, Sofie, Castillo, Sandra D., Brouillard, Pascal, Libbrecht, Louis, Saur, Dieter, Graupera, Mariona, Alitalo, Kari, Boon, Laurence, Vikkula, Miikka, and Mäkinen, Taija
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- 2020
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6. Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation
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Petkova, Milena, Kraft, Marle, Stritt, Simon, Martinez-Corral, Ines, Ortsäter, Henrik, Vanlandewijck, Michael, Jakic, Bojana, Baselga, Eulalia, Castillo, Sandra D., Graupera, Mariona, Betsholtz, Christer, Mäkinen, Taija, Petkova, Milena, Kraft, Marle, Stritt, Simon, Martinez-Corral, Ines, Ortsäter, Henrik, Vanlandewijck, Michael, Jakic, Bojana, Baselga, Eulalia, Castillo, Sandra D., Graupera, Mariona, Betsholtz, Christer, and Mäkinen, Taija
- Abstract
Oncogenic mutations in PIK3CA, encoding p110 alpha-PI3K, are a common cause of venous and lymphatic malformations. Vessel type-specific disease pathogenesis is poorly understood, hampering development of efficient therapies. Here, we reveal a new immune-interacting subtype of Ptx3-positive dermal lymphatic capillary endothelial cells (iLECs) that recruit pro-lymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3ca(H1047R)-driven vascular malformations showed that proliferation was induced in both venous and lymphatic ECs but sustained selectively in LECs of advanced lesions. Single-cell transcriptomics identified the iLEC population, residing at lymphatic capillary terminals of normal vasculature, that was expanded in Pik3ca(H1047R) mice. Expression of pro-inflammatory genes, including monocyte/macrophage chemokine Ccl2, in Pik3ca(H1047R)-iLECs was associated with recruitment of VEGF-C-producing macrophages. Macrophage depletion, CCL2 blockade, or anti-inflammatory COX-2 inhibition limited Pik3ca(H1047R)-driven lymphangiogenesis. Thus, targeting the paracrine crosstalk involving iLECs and macrophages provides a new therapeutic opportunity for lymphatic malformations. Identification of iLECs further indicates that peripheral lymphatic vessels not only respond to but also actively orchestrate inflammatory processes.
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- 2023
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7. Behavioural immune landscapes of inflammation
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Crainiciuc, Georgiana, Palomino-Segura, Miguel, Molina-Moreno, Miguel, Sicilia, Jon, Aragones, David G., Li, Jackson Liang Yao, Madurga, Rodrigo, Adrover, José M., Aroca-Crevillén, Alejandra, Martin-Salamanca, Sandra, del Valle, Alfonso Serrano, Castillo, Sandra D., Welch, Heidi C. E., Soehnlein, Oliver, Graupera, Mariona, Sánchez-Cabo, Fátima, Zarbock, Alexander, Smithgall, Thomas E., Di Pilato, Mauro, Mempel, Thorsten R., Tharaux, Pierre-Louis, González, Santiago F., Ayuso-Sacido, Angel, Ng, Lai Guan, Calvo, Gabriel F., González-Díaz, Iván, Díaz-de-María, Fernando, and Hidalgo, Andrés
- Abstract
Transcriptional and proteomic profiling of individual cells have revolutionized interpretation of biological phenomena by providing cellular landscapes of healthy and diseased tissues1,2. These approaches, however, do not describe dynamic scenarios in which cells continuously change their biochemical properties and downstream ‘behavioural’ outputs3–5. Here we used 4D live imaging to record tens to hundreds of morpho-kinetic parameters describing the dynamics of individual leukocytes at sites of active inflammation. By analysing more than 100,000 reconstructions of cell shapes and tracks over time, we obtained behavioural descriptors of individual cells and used these high-dimensional datasets to build behavioural landscapes. These landscapes recognized leukocyte identities in the inflamed skin and trachea, and uncovered a continuum of neutrophil states inside blood vessels, including a large, sessile state that was embraced by the underlying endothelium and associated with pathogenic inflammation. Behavioural screening in 24 mouse mutants identified the kinase Fgr as a driver of this pathogenic state, and interference with Fgr protected mice from inflammatory injury. Thus, behavioural landscapes report distinct properties of dynamic environments at high cellular resolution.
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- 2024
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8. Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation
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Petkova, Milena, primary, Kraft, Marle, additional, Stritt, Simon, additional, Martinez-Corral, Ines, additional, Ortsäter, Henrik, additional, Vanlandewijck, Michael, additional, Jakic, Bojana, additional, Baselga, Eulàlia, additional, Castillo, Sandra D., additional, Graupera, Mariona, additional, Betsholtz, Christer, additional, and Mäkinen, Taija, additional
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- 2023
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9. Endothelial cell rearrangements during vascular patterning require PI3-kinase-mediated inhibition of actomyosin contractility
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Angulo-Urarte, Ana, Casado, Pedro, Castillo, Sandra D., Kobialka, Piotr, Kotini, Maria Paraskevi, Figueiredo, Ana M., Castel, Pau, Rajeeve, Vinothini, Milà-Guasch, Maria, Millan, Jaime, Wiesner, Cora, Serra, Helena, Muixi, Laia, Casanovas, Oriol, Viñals, Francesc, Affolter, Markus, Gerhardt, Holger, Huveneers, Stephan, Belting, Heinz-Georg, Cutillas, Pedro R., and Graupera, Mariona
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- 2018
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10. Angiocrine polyamine production regulates adiposity
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Monelli, Erika, Villacampa, Pilar, Zabala-Letona, Amaia, Martinez-Romero, Anabel, Llena, Judith, Beiroa, Daniel, Gouveia, Leonor, Chivite, Inigo, Zagmutt, Sebastian, Gama-Perez, Pau, Osorio-Conles, Oscar, Muixi, Laia, Martinez-Gonzalez, Ainara, Castillo, Sandra D., Martin-Martin, Natalia, Castel, Pau, Valcarcel-Jimenez, Lorea, Garcia-Gonzalez, Irene, Villena, Josep A., Fernandez-Ruiz, Sonia, Serra, Dolors, Herrero, Laura, Benedito, Rui, Garcia-Roves, Pablo, Vidal, Josep, Cohen, Paul, Nogueiras, Ruben, Claret, Marc, Carracedo, Arkaitz, Graupera, Mariona, Monelli, Erika, Villacampa, Pilar, Zabala-Letona, Amaia, Martinez-Romero, Anabel, Llena, Judith, Beiroa, Daniel, Gouveia, Leonor, Chivite, Inigo, Zagmutt, Sebastian, Gama-Perez, Pau, Osorio-Conles, Oscar, Muixi, Laia, Martinez-Gonzalez, Ainara, Castillo, Sandra D., Martin-Martin, Natalia, Castel, Pau, Valcarcel-Jimenez, Lorea, Garcia-Gonzalez, Irene, Villena, Josep A., Fernandez-Ruiz, Sonia, Serra, Dolors, Herrero, Laura, Benedito, Rui, Garcia-Roves, Pablo, Vidal, Josep, Cohen, Paul, Nogueiras, Ruben, Claret, Marc, Carracedo, Arkaitz, and Graupera, Mariona
- Abstract
Reciprocal interactions between endothelial cells (ECs) and adipocytes are fundamental to maintain white adipose tissue (WAT) homeostasis, as illustrated by the activation of angiogenesis upon WAT expansion, a process that is impaired in obesity. However, the molecular mechanisms underlying the crosstalk between ECs and adipocytes remain poorly understood. Here, we show that local production of polyamines in ECs stimulates adipocyte lipolysis and regulates WAT homeostasis in mice. We promote enhanced cell-autonomous angiogenesis by deleting Pten in the murine endothelium. Endothelial Pten loss leads to a WAT-selective phenotype, characterized by reduced body weight and adiposity in pathophysiological conditions. This phenotype stems from enhanced fatty acid beta-oxidation in ECs concomitant with a paracrine lipolytic action on adipocytes, accounting for reduced adiposity. Combined analysis of murine models, isolated ECs and human specimens reveals that WAT lipolysis is mediated by mTORC1-dependent production of polyamines by ECs. Our results indicate that angiocrine metabolic signals are important for WAT homeostasis and organismal metabolism. Endothelial cells in white adipose tissue are shown to produce polyamines, which regulate adipocyte lipolysis, thus demonstrating how local angiocrine signals contribute to healthy adipose tissue homeostasis.
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- 2022
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11. Genome wide analysis of protein production load in Trichoderma reesei
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Pakula, Tiina, Nygrén, Heli, Barth, Dorothee, Heinonen, Markus, Castillo, Sandra D., Penttilä, Merja E., and Arvas, Mikko
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transcriptomics ,trichoderma reesei ,flux balance analysis ,RNA sequencing ,protein production ,metabolic modelling ,hypocrea jecorina ,stoichiometric model - Abstract
Background: The filamentous fungus Trichoderma reesei (teleomorph Hypocrea jecorina) is a widely used industrial host organism for protein production. In industrial cultivations, it can produce over 100 g/l of extracellular protein, mostly constituting of cellulases and hemicellulases. In order to improve protein production of T. reesei the transcriptional regulation of cellulases and secretory pathway factors have been extensively studied. However, the metabolism of T. reesei under protein production conditions has not received much attention. Results: To understand the physiology and metabolism of T. reesei under protein production conditions we carried out a well-controlled bioreactor experiment with extensive analysis. We used minimal media to make the data amenable for modelling and three strain pairs to cover different protein production levels. With RNA-sequencing transcriptomics we detected the concentration of the carbon source as the most important determinant of the transcriptome. As the major transcriptional response concomitant to protein production we detected the induction of selected genes that were putatively regulated by xyr1 and were related to protein transport, amino acid metabolism and transcriptional regulation. We found novel metabolic responses such as production of glycerol and a cellotriose-like compound. We then used this cultivation data for flux balance analysis of T. reesei metabolism and demonstrate for the first time the use of genome wide stoichiometric metabolic modelling for T. reesei. We show that our model can predict protein production rate and provides novel insight into the metabolism of protein production. We also provide this unprecedented cultivation and transcriptomics data set for future modelling efforts. Conclusions: The use of stoichiometric modelling can open a novel path for the improvement of protein production in T. reesei. Based on this we propose sulphur assimilation as a major limiting factor of protein production. As an organism with exceptional protein production capabilities modelling of T. reesei can provide novel insight also to other less productive organisms.
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- 2016
12. Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling
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Berenjeno, Inma M., primary, Piñeiro, Roberto, additional, Castillo, Sandra D., additional, Pearce, Wayne, additional, McGranahan, Nicholas, additional, Dewhurst, Sally M., additional, Meniel, Valerie, additional, Birkbak, Nicolai J., additional, Lau, Evelyn, additional, Sansregret, Laurent, additional, Morelli, Daniele, additional, Kanu, Nnennaya, additional, Srinivas, Shankar, additional, Graupera, Mariona, additional, Parker, Victoria E. R., additional, Montgomery, Karen G., additional, Moniz, Larissa S., additional, Scudamore, Cheryl L., additional, Phillips, Wayne A., additional, Semple, Robert K., additional, Clarke, Alan, additional, Swanton, Charles, additional, and Vanhaesebroeck, Bart, additional
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- 2017
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13. Abstract 3034: Determining the profiles and parameters for gene amplification testing of growth factor receptors in lung cancer.
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Pros, Eva, primary, Lantuejoul, Sylvie, additional, Sanchez-Verde, Lydia, additional, Castillo, Sandra D., additional, Suarez-Gauthier, Ana, additional, Conde, Esther, additional, Cigudosa, Juan C., additional, Lopez-Rios, Fernando, additional, Torres-Lanzas, Juan, additional, Castellví, Josep, additional, Ramon y Cajal, Santiago, additional, Brambilla, Elisabeth, additional, and Sanchez-Cespedes, Montse, additional
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- 2013
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14. Novel Transcriptional Targets of the SRY-HMG Box Transcription Factor SOX4 Link Its Expression to the Development of Small Cell Lung Cancer
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Castillo, Sandra D., primary, Matheu, Ander, additional, Mariani, Niccolo, additional, Carretero, Julian, additional, Lopez-Rios, Fernando, additional, Lovell-Badge, Robin, additional, and Sanchez-Cespedes, Montse, additional
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- 2012
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15. Abstract 4019: Identification of SOX4 transcriptional target genes in human lung cancer
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Castillo, Sandra D., primary, Medina, Pedro P., additional, Mariani, Niccolò, additional, and Sanchez-Cespedes, Montse, additional
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- 2011
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16. BRCA2 Polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers
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Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Meeks, Huong D., Song, Honglin, Michailidou, Kyriaki, Bolla, Manjeet K., Dennis, Joe G., Wang, Qin, Barrowdale, Daniel, Frost, Debra, McGuffog, Lesley, Ellis, Steve, Feng, Bingjian, Buys, Saundra S., Hopper, John Llewelyn, Southey, Melissa C., Tesoriero, Andrea A., Investigators, Kconfab Con Fab, James, Paul Andrew, Bruinsma, Fiona J., Campbell, Ian G., Broeks, Annegien, Schmidt, Marjanka K., Hogervorst, Frans B.L., Beckman, Matthias W., Fasching, Peter Andreas, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J., Riboli, Elio, Banerjee, Susana N., Menon, Usha, Tomlinson, Ian, Burwinkel, Barbara, Hamann, Ute, Marmé, Frederik, Rudolph, Anja, Janavičius, Ramūnas, Tihomirova, Laima P., Tung, Nadine M., Garber, Judy Ellen, Cramer, Daniel W., Terry, Kathryn L., Poole, Elizabeth M., Tworoger, Shelley S., Dorfling, Cecilia M., van Rensburg, Elizabeth J., Godwin, Andrew K., Guénel, Pascal, Truong, Thérèse, Stoppa-Lyonnet, Dominique, Damiola, Francesca, Mazoyer, Sylvie, Sinilnikova, Olga M., Isaacs, Claudine J.D., Maugard, Christine M., Bojesen, Stig Egil, Flyger, Henrik Lavlund, Gerdes, Anne Marie, Hansen, Thomas Van Overeem, Jensen, Allan, Kjaer, Susan K., Høgdall, Claus K., Høgdall, Estrid, Pedersen, Inge Søkilde, Thomassen, Mads, Benit́ez, Javier J., González-Neira, Anna, Osorio, Ana, de la Hoya, Miguel, Peréz-Segura, Pedro, Díez-Gibert, Orland, Lázaro, Conxi, Brunet, Joan Maria, Anton-Culver, Hoda, Eunjung, Lee, John, Esther M., Neuhausen, Susan L., Ding, YC, Castillo, Sandra D., Weitzel, JN, Ganz, PA, Nussbaum, RL, Chan, SB, Karlan, BY, Lester, J, Wu, A, Gayther, S, Ramus, SJ, Sieh, W, Whittermore, AS, Monteiro, AN, Phelan, CM, Terry, MB, Piedmonte, M, Offit, K, Robson, M, Levine, D, Moysich, KB, Cannioto, R, Olson, SH, Daly, MB, Nathanson, KL, Domchek, SM, Lu, KH, Liang, D, Hildebrant, MA, Ness, R, Modugno, F, Pearce, L, Goodman, MT, Thompson, PJ, Brenner, H, Butterbach, K, Meindl, A, Hahnen, E, Wappenschmidt, B, Brauch, H, Brüning, T, Blomqvist, C, Khan, S, Nevanlinna, H, Pelttari, LM, Aittomäki, K, Butzow, R, Bogdanova, NV, Dörk, T, Lindblom, A, Margolin, S, Rantala, J, Kosma, VM, Mannermaa, A, Lambrechts, D, Neven, P, Claes, KB, Maerken, TV, Chang-Claude, J, Flesch-Janys, D, Heitz, F, Varon-Mateeva, R, Peterlongo, P, Radice, P, Viel, A, Barile, M, Peissel, B, Manoukian, S, Montagna, M, Oliani, C, Peixoto, A, Teixeira, MR, Collavoli, A, Hallberg, E, Olson, JE, Goode, EL, Hart, SN, Shimelis, H, Cunningham, JM, Giles, GG, Milne, RL, Healey, S, Tucker, K, Haiman, CA, Henderson, BE, Goldberg, MS, Tischkowitz, M, Simard, J, Soucy, P, Eccles, DM, Le, N, Borresen-Dale, AL, Kristensen, V, Salvesen, HB, Bjorge, L, Bandera, EV, Risch, H, Zheng, W, Beeghly-Fadiel, A, Cai, H, Pylkäs, K, Tollenaar, RA, Ouweland, AM, Andrulis, IL, Knight, JA, OCGN, Narod, S, Devilee, P, Winqvist, R, Figueroa, J, Greene, MH, Mai, PL, Loud, JT, García-Closas, M, Schoemaker, MJ, Czene, K, Darabi, H, McNeish, I, Siddiquil, N, Glasspool, R, Kwong, A, Park, SK, Teo, SH, Yoon, SY, Matsuo, K, Hosono, S, Woo, YL, Gao, YT, Foretova, L, Singer, CF, Rappaport-Feurhauser, C, Friedman, E, Laitman, Y, Rennert, G, Imyanitov, EN, Hulick, PJ, Olopade, OI, Senter, L, Olah, E, Doherty, JA, Schildkraut, J, Koppert, LB, Kiemeney, LA, Massuger, LF, Cook, LS, Pejovic, T, Li, J, Borg, A, Öfverholm, A, Rossing, MA, Wentzensen, N, Henriksson, K, Cox, A, Cross, SS, Pasini, BJ, Shah, M, Kabisch, M, Torres, D, Jakubowska, A, Lubinski, J, Gronwald, J, Agnarsson, BA, Kupryjanczyk, J, Moes-Sosnowska, J, Fostira, F, Konstantopoulou, I, Slager, S, Jones, M, PRostate cancer AssoCiation group To Investigate Cancer Associated aLterations in the genome, Antoniou, AC, Berchuck, A, Swerdlow, A, Chenevix-Trench, G, Dunning, AM, Pharoah, PD, Hall, P, Easton, DF, Couch, FJ, Spurdle, AB, Goldgar, DE., Australia Ovarian Cancer Study Group, HEBON, EMBRACE, Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Meeks, Huong D., Song, Honglin, Michailidou, Kyriaki, Bolla, Manjeet K., Dennis, Joe G., Wang, Qin, Barrowdale, Daniel, Frost, Debra, McGuffog, Lesley, Ellis, Steve, Feng, Bingjian, Buys, Saundra S., Hopper, John Llewelyn, Southey, Melissa C., Tesoriero, Andrea A., Investigators, Kconfab Con Fab, James, Paul Andrew, Bruinsma, Fiona J., Campbell, Ian G., Broeks, Annegien, Schmidt, Marjanka K., Hogervorst, Frans B.L., Beckman, Matthias W., Fasching, Peter Andreas, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J., Riboli, Elio, Banerjee, Susana N., Menon, Usha, Tomlinson, Ian, Burwinkel, Barbara, Hamann, Ute, Marmé, Frederik, Rudolph, Anja, Janavičius, Ramūnas, Tihomirova, Laima P., Tung, Nadine M., Garber, Judy Ellen, Cramer, Daniel W., Terry, Kathryn L., Poole, Elizabeth M., Tworoger, Shelley S., Dorfling, Cecilia M., van Rensburg, Elizabeth J., Godwin, Andrew K., Guénel, Pascal, Truong, Thérèse, Stoppa-Lyonnet, Dominique, Damiola, Francesca, Mazoyer, Sylvie, Sinilnikova, Olga M., Isaacs, Claudine J.D., Maugard, Christine M., Bojesen, Stig Egil, Flyger, Henrik Lavlund, Gerdes, Anne Marie, Hansen, Thomas Van Overeem, Jensen, Allan, Kjaer, Susan K., Høgdall, Claus K., Høgdall, Estrid, Pedersen, Inge Søkilde, Thomassen, Mads, Benit́ez, Javier J., González-Neira, Anna, Osorio, Ana, de la Hoya, Miguel, Peréz-Segura, Pedro, Díez-Gibert, Orland, Lázaro, Conxi, Brunet, Joan Maria, Anton-Culver, Hoda, Eunjung, Lee, John, Esther M., Neuhausen, Susan L., Ding, YC, Castillo, Sandra D., Weitzel, JN, Ganz, PA, Nussbaum, RL, Chan, SB, Karlan, BY, Lester, J, Wu, A, Gayther, S, Ramus, SJ, Sieh, W, Whittermore, AS, Monteiro, AN, Phelan, CM, Terry, MB, Piedmonte, M, Offit, K, Robson, M, Levine, D, Moysich, KB, Cannioto, R, Olson, SH, Daly, MB, Nathanson, KL, Domchek, SM, Lu, KH, Liang, D, Hildebrant, MA, Ness, R, Modugno, F, Pearce, L, Goodman, MT, Thompson, PJ, Brenner, H, Butterbach, K, Meindl, A, Hahnen, E, Wappenschmidt, B, Brauch, H, Brüning, T, Blomqvist, C, Khan, S, Nevanlinna, H, Pelttari, LM, Aittomäki, K, Butzow, R, Bogdanova, NV, Dörk, T, Lindblom, A, Margolin, S, Rantala, J, Kosma, VM, Mannermaa, A, Lambrechts, D, Neven, P, Claes, KB, Maerken, TV, Chang-Claude, J, Flesch-Janys, D, Heitz, F, Varon-Mateeva, R, Peterlongo, P, Radice, P, Viel, A, Barile, M, Peissel, B, Manoukian, S, Montagna, M, Oliani, C, Peixoto, A, Teixeira, MR, Collavoli, A, Hallberg, E, Olson, JE, Goode, EL, Hart, SN, Shimelis, H, Cunningham, JM, Giles, GG, Milne, RL, Healey, S, Tucker, K, Haiman, CA, Henderson, BE, Goldberg, MS, Tischkowitz, M, Simard, J, Soucy, P, Eccles, DM, Le, N, Borresen-Dale, AL, Kristensen, V, Salvesen, HB, Bjorge, L, Bandera, EV, Risch, H, Zheng, W, Beeghly-Fadiel, A, Cai, H, Pylkäs, K, Tollenaar, RA, Ouweland, AM, Andrulis, IL, Knight, JA, OCGN, Narod, S, Devilee, P, Winqvist, R, Figueroa, J, Greene, MH, Mai, PL, Loud, JT, García-Closas, M, Schoemaker, MJ, Czene, K, Darabi, H, McNeish, I, Siddiquil, N, Glasspool, R, Kwong, A, Park, SK, Teo, SH, Yoon, SY, Matsuo, K, Hosono, S, Woo, YL, Gao, YT, Foretova, L, Singer, CF, Rappaport-Feurhauser, C, Friedman, E, Laitman, Y, Rennert, G, Imyanitov, EN, Hulick, PJ, Olopade, OI, Senter, L, Olah, E, Doherty, JA, Schildkraut, J, Koppert, LB, Kiemeney, LA, Massuger, LF, Cook, LS, Pejovic, T, Li, J, Borg, A, Öfverholm, A, Rossing, MA, Wentzensen, N, Henriksson, K, Cox, A, Cross, SS, Pasini, BJ, Shah, M, Kabisch, M, Torres, D, Jakubowska, A, Lubinski, J, Gronwald, J, Agnarsson, BA, Kupryjanczyk, J, Moes-Sosnowska, J, Fostira, F, Konstantopoulou, I, Slager, S, Jones, M, PRostate cancer AssoCiation group To Investigate Cancer Associated aLterations in the genome, Antoniou, AC, Berchuck, A, Swerdlow, A, Chenevix-Trench, G, Dunning, AM, Pharoah, PD, Hall, P, Easton, DF, Couch, FJ, Spurdle, AB, Goldgar, DE., Australia Ovarian Cancer Study Group, HEBON, and EMBRACE
17. Oncogenic Phosphoinositide 3-Kinase signalling in Venous Malformations
- Author
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Zanoncello, Jasmina, Castillo, Sandra D., Graupera i Garcia-Milà, Mariona, and Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut
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Venous insufficiency ,Malalties del sistema limfàtic ,Insuficiència venosa ,Lymphatic diseases ,Fosfatidilinositols ,Phosphatidylinositols ,Malalties vasculars ,Vascular diseases - Abstract
[eng] Venous malformations (VM), the most frequent type of vascular malformations, are localized developmental defects occurring during vascular morphogenesis that generat dilated, tortuous venous channels surrounded by erratically distributed mural cells and a disorganized extracellular matrix. VM often manifest sporadically at birth and grow over the time. They can be of different sizes and be present in any tissue resulting in chronic pathologies that are painful and lead to recurrent bleeding, infection and organ dysfunction. Current standard treatments are not fully efficient and are associated with high risk of recurrence and progression, claiming for an urgent need for targeted therapies. From a biological perspective VM are considered as congenital errors affecting endothelial cells (ECs) or early endothelial progenitors, characterized by a constitutive activation of PI3K signalling pathway. Key discovering studies identified mutually exclusive somatic gain-of-function mutations in the endothelial PIK3CA gene or in the upstream endothelial tyrosine-kinase receptor TEK, as the genetic causes generating VM lesions. However, the molecular and cellular mechanisms driven by PI3K signalling activation in ECs underlying the pathogenesis of VM remain unknown. Here, by using an innovative approach that combines untargeted transcriptomics with unique in vitro and in vivo models, we investigated the pathogenic mechanisms induced by the expression of the oncogenic PIK3CA-H1047R activating mutation in ECs. We confirm that ECs hyperproliferation is the triggering mechanism leading to abnormal dilated hyperplastic vascular channels in vivo. In addition, we discover that expression of the mutation induces a unique shift in the adhesive molecular signature of ECs, with a specific impact on the integrins profile, which can be rescued by the use of PI3K pathway inhibitors. Also, Pik3caH1047R expression leads to an increased capacity of ECs to migrate. We postulate that altogether, the combination of an altered proliferative and migratory ECs behaviour causes defects in angiogenesis, showing a novel scenario for the pathogenesis of PI3K-driven VM. We identified the integrin-a9 as the most up-regulated integrin upon Pik3caH1047R expression in ECs and we propose that its role is key in mediating the aberrant ECs behaviour underlying the pathogenesis of VM. Finally, we developed in vivo and in vitro pre-clinical models, which can be used in combination, to study the biology of VM, enabling the investigation and development of new personalized therapies on a patient-to-patient basis.
- Published
- 2020
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