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52. Bone Morphogenetic Protein 9 Protects against Neonatal Hyperoxia-Induced Impairment of Alveolarization and Pulmonary Inflammation

Author

Xueyu Chen, Mar Orriols, Frans J. Walther, El Houari Laghmani, Annemarie M. Hoogeboom, Anne C. B. Hogen-Esch, Pieter S. Hiemstra, Gert Folkerts, Marie-José T. H. Goumans, Peter ten Dijke, Nicholas W. Morrell, and Gerry T. M. Wagenaar

Subjects
bronchopulmonary dysplasia, lung fibrosis, activin receptor-like kinase 1, right ventricular hypertrophy, transmembrane protein 100, Physiology, QP1-981
Abstract

Aim: Effective treatment of premature infants with bronchopulmonary dysplasia (BPD) is lacking. We hypothesize that bone morphogenetic protein 9 (BMP9), a ligand of the TGF-β family that binds to the activin receptor-like kinase 1 (ALK1)-BMP receptor type 2 (BMPR2) receptor complex, may be a novel therapeutic option for BPD. Therefore, we investigated the cardiopulmonary effects of BMP9 in neonatal Wistar rats with hyperoxia-induced BPD.Methods: Directly after birth Wistar rat pups were exposed to 100% oxygen for 10 days. From day 2 rat pups received BMP9 (2.5 μg/kg, twice a day) or 0.9% NaCl by subcutaneous injection. Beneficial effects of BMP9 on aberrant alveolar development, lung inflammation and fibrosis, and right ventricular hypertrophy (RVH) were investigated by morphometric analysis and cytokine production. In addition, differential mRNA expression of BMP9 and its receptor complex: ALK1, BMPR2, and Endoglin, and of the ALK1 downstream target transmembrane protein 100 (TMEM100) were studied during the development of experimental BPD. Expression of the BMP9 receptor complex and TMEM100 was studied in human endothelial and epithelial cell cultures and the effect of BMP9 on inflammatory cytokine production and TMEM100 expression was studied in endothelial cell cultures.Results:ALK1, ALK2, BMPRII, TMEM100, and Endoglin were differentially expressed in experimental BPD, suggesting a role for BMP9-dependent signaling in the development of (experimental) BPD. TMEM100 was expressed in the wall of blood vessels, showing an elastin-like expression pattern in arterioles. Expression of TMEM100 mRNA and protein was decreased after exposure to hyperoxia. BMP9 treatment of rat pups with hyperoxia-induced experimental BPD reduced alveolar enlargement, lung septal thickness and fibrosis, and prevented inflammation, but did not attenuate vascular remodeling and RVH. The anti-inflammatory effect of BMP9 was confirmed in vitro. Highest expression of ALK1, BMPR2, and TMEM100 was observed in human endothelial cell cultures. Stimulation of human endothelial cell cultures with BMP9 reduced their pro-inflammatory cytokine response and induced TMEM100 expression in pulmonary arterial endothelial cells.Conclusion: BMP9 protects against neonatal hyperoxia-induced BPD by improving aberrant alveolar development, inflammation and fibrosis, demonstrating its therapeutic potential for premature infants with severe BPD.

Published
2017
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53. 18th European Symposium on Radiopharmacy and Radiopharmaceuticals: Salzburg, Austria. 7-10 April 2016

Author

Radchenko, V., Engle, J. W., Roy, C., Griswold, J., Nortier, M. F., Birnbaum, E. R., Brugh, M., Mirzadeh, S., John, K. D., Fassbender, M. E., Zhai, Chuangyan, Franssen, Gerben M., Petrik, Milos, Laverman, Peter, Decristoforo, Clemens, Samia, Ait-Mohand, Véronique, Dumulon-Perreault, Brigitte, Guérin, Summer, D., Kroess, A., Rangger, C., Haas, H., Laverman, P., Gerben, F., von Guggenberg, E., Decristoforo, C., Bolzati, Cristina, Salvarese, Nicola, Refosco, Fiorenzo, Meléndez-Alafort, Laura, Carpanese, Debora, Rosato, Antonio, Saviano, Michele, Del Gatto, Annarita, Comegna, Daniela, Zaccaro, Laura, Billaud, Emilie, Ahamed, Muneer, Cleeren, Frederik, Shahbazali, Elnaz, Noël, Tim, Hessel, Volker, Verbruggen, Alfons, Bormans, Guy, Cleeren, F., Lecina, J., Koole, M., Verbruggen, A., Bormans, G., Lugatoa, B., Stucchia, S., Turollaa, E. A., Giulianoa, L., Toddea, S., Ferraboschib, P., Klok, R. P., Mooijer, M. P. J., Hendrikse, N. H., Windhorst, A. D., Collet, C., Petry, N., Chrétien, F., Karcher, G., Pellegrini-Moïse, N., Lamandé-Langle, S., Pfaff, Sarah, Philippe, Cecile, Mitterhauser, Markus, Hacker, Marcus, Wadsak, Wolfgang, Guérard, François, Lee, Yong-Sok, Gouard, Sébastien, Baidoo, Kwamena, Alliot, Cyrille, Chérel, Michel, Brechbiel, Martin W., Gestin, Jean-François, Lam, K., Chan, C., Reilly, R. M., Paillas, Salomé, Marshall, John, Pouget, Jean-Pierre, Sosabowski, Jane, Briard, Emmanuelle, Auberson, Yves P., Reilly, John, Healy, Mark, Sykes, David, Paulus, Andreas, Lichtenbelt, Wouter van Marken, Mottaghy, Felix, Bauwens, Matthias, Baranski, Ann-Christin, Schäfer, Martin, Bauder-Wüst, Ulrike, Haberkorn, Uwe, Eder, Matthias, Kopka, Klaus, Chaussard, M., Hosten, B., Vignal, N., Tsoupko-Sitnikov, V., Hernio, N., Hontonnou, F., Merlet, P., Poyet, J. L., Sarda-Mantel, L., Rizzo-Padoin, N., Cardinale, J., Schäfer, M., Benešová, M., Bauder-Wüst, U., Seibert, O., Giesel, F., Haberkorn, U., Eder, M., Kopka, K., Nematallah, Mansour, Michel, Paquette, Samia, Ait-Mohand, Véronique, Dumulon-Perreault, Roger, Lecomte, Brigitte, Guérin, Fernandez-Maza, L., Rivera-Marrero, S., Capote, A. Prats, Parrado-Gallego, A., Fernandez-Gomez, I., Balcerzyk, M., Sablon-Carrazana, M., Perera-Pintado, A., Merceron-Martinez, D., Acosta-Medina, E., Rodriguez-Tanty, C., Attili, Bala, Ahamed, Muneer, Bormans, Guy, Philippe, C., Zeilinger, M., Scherer, T., Fürnsinn, C., Dumanic, M., Wadsak, W., Hacker, M., Mitterhauser, M., Janssen, B., Vugts, D. J., Molenaar, G.T. T., Funke, U., Kruijer, P. S., Dollé, F., Bormans, G., Lammertsma, A. A., Windhorst, A. D., Vermeulen, Koen, Ahamed, Muneer, Schnekenburger, Michael, Froeyen, Mathy, Olberg, Dag Erlend, Diederich, Marc, Bormansa, Guy, Raaphorst, R. M., Luurtsema, G., Lammertsma, A. A., Elsinga, P. H., Windhorst, A D., Rotteveel, Lonneke, Funke, Uta, ten Dijke, Peter, Bogaard, Harm Jan, Lammertsma, Adriaan A., Windhorst, Albert D., Song, Lei, Able, Sarah, Falzone, Nadia, Kersemans, Veerle, Vallis, Katherine, Carta, Davide, Salvarese, Nicola, Sihver, Wiebke, Gao, Feng, Pietzsch, Hans Jürgen, Biondi, Barbara, Ruzza, Paolo, Refosco, Fiorenzo, Bolzati, Cristina, Haubner, Roland, Finkensted, Armin, Stegmair, Armin, Rangger, Christine, Decristoforo, Clemens, Zoller, Heinz, Virgolini, Irene J., Pooters, Ivo, Lotz, Maartje, Wierts, Roel, Mottaghy, Felix, Bauwens, Matthias, Forsback, Sarita, Jörgen, Bergman, Riikka, Kivelä, Karageorgou, M., Radović, M., Tsoukalas, C., Antic, B., Gazouli, M., Paravatou-Petsotas, M., Xanthopouls, S., Calamiotou, M., Stamopoulos, D., Vranješ-Durić, S., Bouziotis, P., Lunev, A. S., Larenkov, A. A., Petrosova, K. A., Klementyeva, O. E., Kodina, G. E., Kvernenes, O. H., Adamsen, T. C. H., Martin, René, Weidlich, Sebastian, Zerges, Anna-Maria, Gameiro, Cristiana, Lazarova, Neva, Müllera, Marco, Luurtsema, Gert, de Vries, Michèl, Ghyoot, Michel, van der Woude, Gina, Zijlma, Rolf, Dierckx, Rudi, Boersma, Hendrikus H., Elsinga, Philip H., Lambrecht, Fatma Yurt, Er, Ozge, Ince, Mine, Avci, Cıgır Biray, Gunduz, Cumhur, Sarı, Fatma Aslihan, Ocakoglu, Kasim, Er, Ozge, Ersoz, Onur Alp, Lambrecht, Fatma Yurt, Ince, Mine, Kayabasi, Cagla, Gunduz, Cumhur, Kniess, Torsten, Meister, Sebastian, Fischer, Steffen, Steinbach, Jörg, Ashfaq, Rabia, Iqbal, Saeed, ullah Khan, Irfan, Iglesias-Jerez, R., Martín-Banderas, L., Perera-Pintado, A., Borrego-Dorado, I., Farinha-Antunes, Ines, Kwizera, Chantal, Lacivita, Enza, Lucente, Ermelinda, Niso, Mauro, De Giorgio, Paola, Perrone, Roberto, Colabufo, Nicola A., Elsinga, Philip H., Leopoldo, Marcello, Vaulina, V. V., Fedorova, O. S., Orlovskaja, V. V., Chen, С. L., Li, G. Y., Meng, F. C., Liu, R. S., Wang, H. E., Krasikova, R. N., Meléndez-Alafort, Laura, Abozeid, Mohamed, Ferro-Flores, Guillermina, Negri, Anna, Bello, Michele, Uzunov, Nikolay, Paiusco, Martha, Esposito, Juan, Rosato, Antonio, Meléndez-Alafort, Laura, Bolzati, Cristina, Ferro-Flores, Guillermina, Salvarese, Nicola, Carpanese, Debora, Abozeid, Mohamed, Rosato, Antonio, Uzunov, Nikolay, Palmieri, L., Verbrugghen, T., Glassner, M., Hoogenboom, R., Staelens, S., Wyffels, L., Orlovskaja, V. V., Kuznetsova, O. F., Fedorova, O. S., Maleev, V. I., Belokon, Yu. N., Geolchanyan, A., Saghyan, A. S., Mu, L., Schibli, R., Ametamey, S. M., Krasikova, R. N., Revunov, Evgeny, Malmquist, Jonas, Johnström, Peter, Van Valkenburgh, Juno, Steele, Dalton, Halldin, Christer, Schou, Magnus, Osati, Samira, Paquette, Michel, Beaudoin, Simon, Ali, Hasrat, Guerin, Brigitte, Leyton, Jeffrey V., van Lier, Johan E., Di Iorio, V, Iori, M., Donati, C., Lanzetta, V., Capponi, P. C., Rubagotti, S., Dreger, T., Kunkel, F., Asti, M., Zhai, Chuangyan, Rangger, Christine, Summer, Dominik, Haas, Hubertus, Decristoforo, Clemens, Kijprayoon, Suphansa, Ruangma, Ananya, Ngokpol, Suthatip, Tuamputsha, Samart, Filp, Ulrike, Pees, Anna, Taddei, Carlotta, Pekošak, Aleksandra, Gee, Antony D., Poot, Alex J., Windhorst, Albert D., Gunay, Mine Silindir, Ozer, A. Yekta, Erdogan, Suna, Baysal, Ipek, Guilloteau, Denis, Chalon, Sylvie, Galli, Filippo, Artico, Marco, Taurone, Samanta, Bianchi, Enrica, Weintraub, Bruce D., Skudlinski, Mariusz, Signore, Alberto, Lepareur, Nicolas, Noiret, Nicolas, Hindré, François, Lacœuille, Franck, Benoist, Eric, Garin, Etienne, Trejo-Ballado, F., Zamora-Romo, E., Manrique-Arias, J. C., Gama-Romero, H M, Contreras-Castañon, G., Tecuapetla-Chantes, R. G., Avila-Rodriguez, M. A., Kvaternik, H., Hausberger, D., Zink, C., Rumpf, B., Aigner, R. M., Kvaternik, H., Hausberger, D., Rumpf, B., Aigner, R. M., Janković, Drina, Lakić, Mladen, Savić, Aleksandar, Ristić, Slavica, Nikolić, Nadežda, Vukadinović, Aleksandar, Sabo, Tibor J., Vranješ-Đurić, Sanja, Vranješ-Đurić, S., Radović, M., Janković, D., Nikolić, N., Goya, G. F., Calatayud, P., Spasojević, V., Antić, B., Goblet, David, Gameiro, Cristiana, Lazarova, Neva, Gameiro, Cristiana, Oxley, Ian, Abrunhosa, Antero, Kramer, Vasko, Vosjan, Maria, Spaans, Arnold, Vats, Kusum, Satpati, Drishty, Sarma, Haladhar D., Banerjee, Sharmila, Wojdowska, W., Pawlak, D. W., Parus, L. J., Garnuszek, P., Mikołajczak, R., Pijarowska-Kruszyna, J., Jaron, A., Kachniarz, A., Malkowski, B., Garnuszek, P., Mikolajczak, R., Ilem-Ozdemir, Derya, Caglayan-Orumlu, Oya, Asikoglu, Makbule, Ilem-Ozdemir, Derya, Caglayan-Orumlu, Oya, Asikoglu, Makbule, Eveliina, Arponen, Semi, Helin, Timo, Saarinen, Simo, Vauhkala, Esa, Kokkomäki, Pertti, Lehikoinen, De Simone, Mariarosaria, Pascali, Giancarlo, Carzoli, Ludovica, Quaglierini, Mauro, Telleschi, Mauro, Salvadori, Piero A., Lam, Phoebe, Aistleitner, Martina, Eichinger, Reinhard, Artner, Christoph, Nakka, Surendra, MC, Hemantha Kumara, Al-Qahtani, Mohammed, Al-Qahtani, Mohammed, Al-Malki, Yousif, Mambilima, N., Rubow, S. M., Berroterán-Infante, N., Hacker, M., Mitterhauser, M., Wadsak, W., Funke, Uta, Cleeren, Frederik, Lecina, Joan, Gallardo, Rodrigo, Verbruggen, Alfons M., Bormans, Guy, Ramos-Membrive, Rocío, Brotons, Ana, Quincoces, Gemma, Inchaurraga, Laura, de Redín, Inés Luis, Morán, Verónica, García-García, Berta, Irache, Juan Manuel, Peñuelas, Iván, Trabelsi, M., Cooper, M. S., Abella, Alejandra, Fuente, Teodomiro, Montellano, Antonio Jesús, Martínez, Teresa, Rabadan, Ruben, Meseguer-Olmo, Luis, Lehtiniemi, P., Yim, C., Mikkola, K., Nuutila, P., Solin, O., von Guggenberg, E., Rangger, C., Mair, C., Balogh, L., Pöstényi, Z., Pawlak, D., Mikołajczak, R., Socan, A., Peitl, P. Kolenc, Krošelj, M., Rangger, C., Decristoforo, C., Collet, C., Remy, S., Didier, R., Vergote, T., Karcher, G., Véran, N., Pawlak, D., Maurin, M., Garnuszek, P., Karczmarczyk, U., Mikołajczak, R., Fredericia, Pil, Severin, Gregory, Groesser, Torsten, Köster, Ulli, Jensen, Mikael, Leonte, R., Puicea, F. D., Raicu, A., Min, E. A., Serban, R., Manda, G., Niculae, D., Zerna, Marion, Schieferstein, Hanno, Müller, Andre, Berndt, Mathias, Yim, Cheng-Bin, Mikkola, Kirsi, Nuutila, Pirjo, Solin, Olof, Seifert, D., Ráliš, J., Lebeda, O., Selivanova, Svetlana V., Senta, Helena, Lavallée, Éric, Caouette, Lyne, Turcotte, Éric, Lecomte, Roger, Kochovska, Marina Zdraveska, Ivanovska, Emilija Janjevik, Jokic, Vesna Spasic, Ackova, Darinka Gjorgieva, Smilkov, Katarina, Makreski, Petre, Stafilov, Trajče, Janevik-Ivanovska, Emilija, Alemu, Aschalew, Muchira, Joel Munene, Wanjeh, David Mwanza, Janevik-Ivanovska, Emilija, Janevik-Ivanovska, Emilija, Zdravev, Zoran, Bhonsle, Uday, Alberto, Osso Júnior João, Duatti, Adriano, Angelovska, Bistra, Stojanovska, Zdenka, Sarafinovska, Zorica Arsova, Bosnakovski, Darko, Gorgieva-Ackova, Darinka, Smilkov, Katarina, Drakalska, Elena, Venkatesh, Meera, Gulaboski, Rubin, Colin, Didier J., Inkster, James A. H., Germain, Stéphane, Seimbille, Yann, Atiq-ur-Rehman, and Cayero-Otero

Published
2016
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55. A Novel Pancreatic Cancer Mini-tumor Model to Study Desmoplasia and Myofibroblastic Cancer-Associated Fibroblast Differentiation

Author

Harryvan, T.J., Hawinkels, L.J.A.C., Östman, A., ten Dijke, P., Strell, Carina, Hornsveld, M., Inderson, A., van Hooft, J.E., Micke, Patrick, Johansen, J.S., van Wezel, T., Crobach, S., Baart, V.M., Quist, B.S., Roet, J.E.G., Kop, M.E., Harryvan, T.J., Hawinkels, L.J.A.C., Östman, A., ten Dijke, P., Strell, Carina, Hornsveld, M., Inderson, A., van Hooft, J.E., Micke, Patrick, Johansen, J.S., van Wezel, T., Crobach, S., Baart, V.M., Quist, B.S., Roet, J.E.G., and Kop, M.E.

Published
2022
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56. A Novel Pancreatic Cancer Mini-tumor Model to Study Desmoplasia and Myofibroblastic Cancer-Associated Fibroblast Differentiation

Author

Harryvan, T.J., primary, Hawinkels, L.J.A.C., additional, Östman, A., additional, ten Dijke, P., additional, Strell, C., additional, Hornsveld, M., additional, Inderson, A., additional, van Hooft, J.E., additional, Micke, P., additional, Johansen, J.S., additional, van Wezel, T., additional, Crobach, S., additional, Baart, V.M., additional, Quist, B.S., additional, Roet, J.E.G., additional, and Kop, M.E., additional

Published
2022
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62. Dissection of N-, O- and glycosphingolipid glycosylation changes in PaTu-S pancreatic adenocarcinoma cells upon TGF-β challenge

Author

Manfred Wuhrer, Tao Zhang, Jing Zhang, Constantin Blöchl, Katarina Madunić, Stephanie Holst, Zejian Zhang, and ten Dijke P

Subjects
carbohydrates (lipids), chemistry.chemical_compound, Glycosylation, Globoside, Tumor progression, Chemistry, Cell culture, Tn antigen, Beta (finance), Molecular biology, Fucosylation, Transforming growth factor
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and high mortality. Transforming growth factor-β (TGF-β) plays a key role in tumor progression, which is often associated with aberrant glycosylation. How PDAC cells respond to TGF-β and the role of glycosylation therein is, however, not well known. Here, we investigated the TGF-β-mediated response and glycosylation changes in SMAD4-deficient PaTu-8955S (PaTu-S) cell line. PaTu-S cells responded to TGF-β by upregulating SMAD2 phosphorylation and target gene expression. TGF-β induced expression of the mesenchymal marker N-cadherin, but did not significantly affect epithelial marker E-cadherin expression. The differences of N-glycans, O-glycans and glycosphingolipid (GSL) glycans in PaTu-S cells with TGF-β stimulation were examined. TGF-β treatment primarily induced N-glycome aberrations involving elevated levels of branching, core fucosylation, and sialylation in PaTu-S cells, in line with TGF-β-induced changes in the expression of glycosylation-related genes. In addition, we observed differences in O- and GSL-glycosylation profiles after TGF-β treatment, including lower levels of sialylated Tn antigen, and neoexpression of globosides. Furthermore, SOX4 expression was upregulated upon TGF-β stimulation, and its depletion blocked the TGF-β-induced N-glycomic changes. Thus, our study provides a mechanism by which TGF-β-induced N-glycosylation changes in SOX4 dependent and SMAD4 independent manner in pancreatic cancer cells. Our results open up avenues to study the relevance of glycosylation in TGF-β signaling in SMAD4 inactivated PDAC.

Published
2021

68. Cancer associated-fibroblast-derived exosomes in cancer progression

Author

Li, C, Teixeira, AF, Zhu, H-J, ten Dijke, P, Li, C, Teixeira, AF, Zhu, H-J, and ten Dijke, P

Abstract

To identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient.

Published
2021

69. A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis

Author

Li, L, Ugalde, AP, Scheele, C, Dieter, SM, van der Nagel, R, Ma, J, Pataskar, A, Korkmaz, G, Elkon, R, Chien, Miao, You, Li, Su, Pin-Rui, Bleijerveld, OB (Onno), Altelaar, M, Momchev, L, Manber, Z, Han, R Q, van Breugel, P C, Lopes, R (Rui Filipe Marques), ten Dijke, P, van Rheenen, J, Agami, Reuven, Li, L, Ugalde, AP, Scheele, C, Dieter, SM, van der Nagel, R, Ma, J, Pataskar, A, Korkmaz, G, Elkon, R, Chien, Miao, You, Li, Su, Pin-Rui, Bleijerveld, OB (Onno), Altelaar, M, Momchev, L, Manber, Z, Han, R Q, van Breugel, P C, Lopes, R (Rui Filipe Marques), ten Dijke, P, van Rheenen, J, and Agami, Reuven

Abstract

Background: Frequent activation of the co-transcriptional factor YAP is observed in a large number of solid tumors. Activated YAP associates with enhancer loci via TEAD4-DNA-binding protein and stimulates cancer aggressiveness. Although thousands of YAP/TEAD4 binding-sites are annotated, their functional importance is unknown. Here, we aim at further identification of enhancer elements that are required for YAP functions. Results: We first apply genome-wide ChIP profiling of YAP to systematically identify enhancers that are bound by YAP/TEAD4. Next, we implement a genetic approach to uncover functions of YAP/TEAD4-associated enhancers, demonstrate its robustness, and use it to reveal a network of enhancers required for YAP-mediated proliferation. We focus on EnhancerTRAM2, as its target gene TRAM2 shows the strongest expression-correlation with YAP activity in nearly all tumor types. Interestingly, TRAM2 phenocopies the YAP-induced cell proliferation, migration, and invasion phenotypes and correlates with poor patient survival. Mechanistically, we identify FSTL-1 as a major direct client of TRAM2 that is involved in these phenotypes. Thus, TRAM2 is a key novel mediator of YAP-induced oncogenic proliferation and cellular invasiveness. Conclusions: YAP is a transcription co-factor that binds to thousands of enhancer loci and stimulates tumor aggressiveness. Using unbiased functional approaches, we dissect YAP enhancer network and characterize TRAM2 as a novel mediator of cellular proliferation, migration, and invasion. Our findings elucidate how YAP induces cancer aggressiveness and may assist diagnosis of cancer metastasis.

Published
2021

79. Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva.

Author

Songting Shi, Jie Cai, David J J de Gorter, Gonzalo Sanchez-Duffhues, Dwi U Kemaladewi, Willem M H Hoogaars, Annemieke Aartsma-Rus, Peter A C 't Hoen, and Peter ten Dijke

Subjects
Medicine, Science
Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare heritable disease characterized by progressive heterotopic ossification of connective tissues, for which there is presently no definite treatment. A recurrent activating mutation (c.617G→A; R206H) of activin receptor-like kinase 2 (ACVR1/ALK2), a BMP type I receptor, has been shown as the main cause of FOP. This mutation constitutively activates the BMP signaling pathway and initiates the formation of heterotopic bone. In this study, we have designed antisense oligonucleotides (AONs) to knockdown mouse ALK2 expression by means of exon skipping. The ALK2 AON could induce exon skipping in cells, which was accompanied by decreased ALK2 mRNA levels and impaired BMP signaling. In addition, the ALK2 AON potentiated muscle differentiation and repressed BMP6-induced osteoblast differentiation. Our results therefore provide a potential therapeutic approach for the treatment of FOP disease by reducing the excessive ALK2 activity in FOP patients.

Published
2013
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84. Surface topography is a context-dependent activator of TGF-β signaling in mesenchymal stem cells

Author

Dede Eren A, Nadia J. T. Roumans, Aliaksei S Vasilevich, Aurélie Carlier, de Boer J, Steven Vermeulen, Floris Honig, Dennie G. A. J. Hebels, and ten Dijke P

Subjects
Activator (genetics), Chemistry, Mesenchymal stem cell, Scleraxis, EGR1, Phosphorylation, SMAD, Mechanotransduction, Serum Response Element, Cell biology
Abstract

We previously found that surface topographies induce the expression of theScxagene, encoding Scleraxis in tenocytes. BecauseScxais a TGF-β responsive gene, we investigated the link between mechanotransduction and TGF-β signaling. We discovered that mesenchymal stem cells exposed to both micro-topographies and TGF-β2 display synergistic induction of SMAD phosphorylation and transcription of the TGF-β target genesSCXA,a-SMA, andSOX9. Pharmacological perturbations revealed that Rho/ROCK/SRF signaling is required for this synergistic response. We further found an activation of the early response genesSRFandEGR1during the early adaptation phase on micro-topographies, which coincided with higher expression of the TGF-β type-II receptor gene. Of interest, PKC activators Prostratin and Ingenol-3, known for inducing actin reorganization and activation of serum response elements, were able to mimic the topography-induced TGF-β response. These findings provide novel insights into the convergence of mechanobiology and TGF-β signaling, which can lead to improved culture protocols and therapeutic applications.

Published
2020
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95. Generation of Fibrodysplasia ossificans progressiva and control integration free iPSC lines from periodontal ligament fibroblasts

Author

Sanchez-Duffhues, G., primary, Mikkers, H., additional, de Jong, D., additional, Szuhai, K., additional, de Vries, T.J., additional, Freund, C., additional, Bravenboer, N., additional, van Es, R.J.J., additional, Netelenbos, J.C., additional, Goumans, M.-.J., additional, Eekhoff, E.M.W., additional, and ten Dijke, P., additional

Published
2019
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98. Author Correction: c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression (Nature Communications, (2019), 10, 1, (4349), 10.1038/s41467-019-12241-2)

Author

Sim, W.J., Iyengar, P.V., Lama, D., Lui, S.K.L., Ng, H.C., Haviv-Shapira, L., Domany, E., Kappei, D., Tan, T.Z., Saei, A., Jaynes, P.W., Verma, C.S., Kumar, A.P., Rouanne, M., Ha, H.K., Radulescu, C., ten Dijke, P., Eichhorn, Pieter, Thiery, J.P., Sim, W.J., Iyengar, P.V., Lama, D., Lui, S.K.L., Ng, H.C., Haviv-Shapira, L., Domany, E., Kappei, D., Tan, T.Z., Saei, A., Jaynes, P.W., Verma, C.S., Kumar, A.P., Rouanne, M., Ha, H.K., Radulescu, C., ten Dijke, P., Eichhorn, Pieter, and Thiery, J.P.

Abstract

© 2019, The Author(s). The original version of this Article contained an error in the spelling of the author Azad Saei, which was incorrectly given as Azad Saie. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

99. c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression

Author

Sim, W.J., Iyengar, P.V., Lama, D., Lui, S.K.L., Ng, H.C., Haviv-Shapira, L., Domany, E., Kappei, D., Tan, T.Z., Saie, A., Jaynes, P.W., Verma, C.S., Kumar, A.P., Rouanne, M., Ha, H.K., Radulescu, C., ten Dijke, P., Eichhorn, Pieter, Thiery, J.P., Sim, W.J., Iyengar, P.V., Lama, D., Lui, S.K.L., Ng, H.C., Haviv-Shapira, L., Domany, E., Kappei, D., Tan, T.Z., Saie, A., Jaynes, P.W., Verma, C.S., Kumar, A.P., Rouanne, M., Ha, H.K., Radulescu, C., ten Dijke, P., Eichhorn, Pieter, and Thiery, J.P.

Abstract

Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.

Published
2019

100. Generation of Fibrodysplasia ossificans progressiva and control integration free iPSC lines from periodontal ligament fibroblasts

Author

Sanchez-Duffhues, G., Mikkers, H., de Jong, D., Szuhai, K., de Vries, T. J., Freund, C., Bravenboer, N., van Es, R. J.J., Netelenbos, J. C., Goumans, M. J., Eekhoff, E. M.W., ten Dijke, P., Sanchez-Duffhues, G., Mikkers, H., de Jong, D., Szuhai, K., de Vries, T. J., Freund, C., Bravenboer, N., van Es, R. J.J., Netelenbos, J. C., Goumans, M. J., Eekhoff, E. M.W., and ten Dijke, P.

Published
2019

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