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1. Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex

Author

Roehrig, Anne E, Klupsch, Kristina, Oses-Prieto, Juan A, Chaib, Selim, Henderson, Stephen, Emmett, Warren, Young, Lucy C, Surinova, Silvia, Blees, Andreas, Pfeiffer, Anett, Tijani, Maha, Brunk, Fabian, Hartig, Nicole, Muñoz-Alegre, Marta, Hergovich, Alexander, Jennings, Barbara H, Burlingame, Alma L, and Rodriguez-Viciana, Pablo

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Rare Diseases, Neurofibromatosis, Neurosciences, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, Cancer, Cell Adhesion, Cell Proliferation, Chromatin, Chromatin Assembly and Disassembly, Contact Inhibition, DNA Helicases, DNA-Binding Proteins, Gene Expression Regulation, HEK293 Cells, Humans, Neoplasms, Neurofibromin 2, Protein Binding, Protein Interaction Maps, Signal Transduction, Tumor Suppressor Proteins, General Science & Technology
Abstract

The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of contact inhibition but the molecular mechanisms remain unclear. In this study we have used affinity proteomics to identify novel Merlin interacting proteins and show that Merlin forms a complex with multiple proteins involved in RNA processing including the PAFC and the CHD1 chromatin remodeller. Tumour-derived inactivating mutations in both Merlin and the CDC73 PAFC subunit mutually disrupt their interaction and growth suppression by Merlin requires CDC73. Merlin interacts with the PAFC in a cell density-dependent manner and we identify a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, Merlin is part of a tumour suppressor network regulated by cell-cell adhesion which coordinates post-initiation steps of the transcription cycle of genes mediating contact inhibition.

Published
2021

2. The Strength of Absent Ties: Social Integration via Online Dating

Author

Ortega, Josue and Hergovich, Philipp

Subjects
Physics - Physics and Society, Computer Science - Social and Information Networks, Economics - General Economics, 91D30, J.4
Abstract

We used to marry people to whom we were somehow connected. Since we were more connected to people similar to us, we were also likely to marry someone from our own race. However, online dating has changed this pattern; people who meet online tend to be complete strangers. We investigate the effects of those previously absent ties on the diversity of modern societies. We find that social integration occurs rapidly when a society benefits from new connections. Our analysis of state-level data on interracial marriage and broadband adoption (proxy for online dating) suggests that this integration process is significant and ongoing.

Published
2017

3. LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function

Author

Fengyuan Tang, Ruize Gao, Beena Jeevan-Raj, Christof B. Wyss, Ravi K. R. Kalathur, Salvatore Piscuoglio, Charlotte K. Y. Ng, Sravanth K. Hindupur, Sandro Nuciforo, Eva Dazert, Thomas Bock, Shuang Song, David Buechel, Marco F. Morini, Alexander Hergovich, Patrick Matthias, Dae-Sik Lim, Luigi M. Terracciano, Markus H. Heim, Michael N. Hall, and Gerhard Christofori

Subjects
Science
Abstract

The autophagic and Hippo pathways are both well characterized contributors to cancer. Here, Tang et al show that LATS1, but not LATS2, negatively regulates autophagy by promoting Beclin1 ubiquitination, which restricts lethal autophagy induced by sorafenib treatment in cancer cells.

Published
2019
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5. Contributors

Author

Barr, John N., primary, Bilichak, Andriy, additional, Boteva, Lora, additional, Brownlee, Peter M., additional, Cherkasova, Viktoriia, additional, Domingo-Calap, P., additional, Durley, Samuel C., additional, Elliott, Amy, additional, Fearns, Rachel, additional, Ferguson, L.R., additional, Firsanov, D.V., additional, Gerasymchuk, M., additional, Gilbert, Nick, additional, Golubov, Andrey, additional, Gómez, V., additional, Goodarzi, Aaron A., additional, Gundogdu, R., additional, Hergovich, A., additional, Hernandez-Sanchez, Wilnelly, additional, Huang, Wei, additional, Humphrey, Timothy C., additional, Izumi, Tadahide, additional, Jones, Rebecca E., additional, Karunasinghe, N., additional, Korda Holsclaw, Julie, additional, Kovalchuk, Igor, additional, Kovalchuk, Olga, additional, Kulaberoglu, Y., additional, Kulikova, V.A., additional, Lopez, Bernard S., additional, Matos-Rodrigues, Gabriel, additional, Mellon, Isabel, additional, Merrifield, Matt, additional, Mikhailov, V.M., additional, Moskwa, Patryk, additional, Mothersill, Carmel, additional, Negishi, Tomoe, additional, Niehaus, Claire, additional, Nikiforov, A.A., additional, Pearson, Dustin D., additional, Provencher, Luc, additional, Ragu, Sandrine, additional, Riabowol, Karl, additional, Rusin, Andrej, additional, Sanjuán, R., additional, Sekelsky, Jeff, additional, Seymour, Colin, additional, Solovjeva, L.V., additional, Svetlova, M.P., additional, Tallen, Gesche, additional, Taylor, Derek J., additional, Thomas, Melissa, additional, Tremaglio, Chadene Z., additional, Xu, Mengyuan, additional, Yadav, Narendra Singh, additional, and Yang, Yang, additional

Published
2021
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7. NDR2 kinase contributes to cell invasion and cytokinesis defects induced by the inactivation of RASSF1A tumor-suppressor gene in lung cancer cells

Author

Maureen Keller, Fatéméh Dubois, Sylvain Teulier, Alexandre P. J. Martin, Jérôme Levallet, Elodie Maille, Solenn Brosseau, Nicolas Elie, Alexander Hergovich, Emmanuel Bergot, Jacques Camonis, Gérard Zalcman, and Guénaëlle Levallet

Subjects
RASSF1A, GEF-H1, YAP, NDR2 kinase, Lung cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background RASSF1A, a tumor suppressor gene, is frequently inactivated in lung cancer leading to a YAP-dependent epithelial-mesenchymal transition (EMT). Such effects are partly due to the inactivation of the anti-migratory RhoB GTPase via the inhibitory phosphorylation of GEF-H1, the GDP/GTP exchange factor for RhoB. However, the kinase responsible for RhoB/GEF-H1 inactivation in RASSF1A-depleted cells remained unknown. Methods NDR1/2 inactivation by siRNA or shRNA effects on epithelial-mesenchymal transition, invasion, xenograft formation and growth in SCID−/− Beige mice, apoptosis, proliferation, cytokinesis, YAP/TAZ activation were investigated upon RASSF1A loss in human bronchial epithelial cells (HBEC). Results We demonstrate here that depletion of the YAP-kinases NDR1/2 reverts migration and metastatic properties upon RASSF1A loss in HBEC. We show that NDR2 interacts directly with GEF-H1 (which contains the NDR phosphorylation consensus motif HXRXXS/T), leading to GEF-H1 phosphorylation. We further report that the RASSF1A/NDR2/GEF-H1/RhoB/YAP axis is involved in proper cytokinesis in human bronchial cells, since chromosome proper segregation are NDR-dependent upon RASSF1A or GEF-H1 loss in HBEC. Conclusion To summarize, our data support a model in which, upon RASSF1A silencing, NDR2 gets activated, phosphorylates and inactivates GEF-H1, leading to RhoB inactivation. This cascade induced by RASSF1A loss in bronchial cells is responsible for metastasis properties, YAP activation and cytokinesis defects.

Published
2019
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8. Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex.

Author

Anne E Roehrig, Kristina Klupsch, Juan A Oses-Prieto, Selim Chaib, Stephen Henderson, Warren Emmett, Lucy C Young, Silvia Surinova, Andreas Blees, Anett Pfeiffer, Maha Tijani, Fabian Brunk, Nicole Hartig, Marta Muñoz-Alegre, Alexander Hergovich, Barbara H Jennings, Alma L Burlingame, and Pablo Rodriguez-Viciana

Subjects
Medicine, Science
Abstract

The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of contact inhibition but the molecular mechanisms remain unclear. In this study we have used affinity proteomics to identify novel Merlin interacting proteins and show that Merlin forms a complex with multiple proteins involved in RNA processing including the PAFC and the CHD1 chromatin remodeller. Tumour-derived inactivating mutations in both Merlin and the CDC73 PAFC subunit mutually disrupt their interaction and growth suppression by Merlin requires CDC73. Merlin interacts with the PAFC in a cell density-dependent manner and we identify a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, Merlin is part of a tumour suppressor network regulated by cell-cell adhesion which coordinates post-initiation steps of the transcription cycle of genes mediating contact inhibition.

Published
2021
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9. LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function

Author

Tang, Fengyuan, Gao, Ruize, Jeevan-Raj, Beena, Wyss, Christof B., Kalathur, Ravi K. R., Piscuoglio, Salvatore, Ng, Charlotte K. Y., Hindupur, Sravanth K., Nuciforo, Sandro, Dazert, Eva, Bock, Thomas, Song, Shuang, Buechel, David, Morini, Marco F., Hergovich, Alexander, Matthias, Patrick, Lim, Dae-Sik, Terracciano, Luigi M., Heim, Markus H., Hall, Michael N., and Christofori, Gerhard

Published
2019
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13. Stable MOB1 interaction with Hippo/MST is not essential for development and tissue growth control

Author

Yavuz Kulaberoglu, Kui Lin, Maxine Holder, Zhongchao Gai, Marta Gomez, Belul Assefa Shifa, Merdiye Mavis, Lily Hoa, Ahmad A. D. Sharif, Celia Lujan, Ewan St. John Smith, Ivana Bjedov, Nicolas Tapon, Geng Wu, and Alexander Hergovich

Subjects
Science
Abstract

The Hippo tumor suppressor pathway is essential for development and tissue growth control. Here the authors employ a multi-disciplinary approach to characterize the interactions of the three Hippo kinases with the signaling adaptor MOB1 and show how they differently affect development, tissue growth and tumor suppression.

Published
2017
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14. Supplementary Table 1 from Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

Author

Flanagan, James M., primary, Wilson, Angela, primary, Koo, Chail, primary, Masrour, Nahal, primary, Gallon, John, primary, Loomis, Erick, primary, Flower, Kirsty, primary, Wilhelm-Benartzi, Charlotte, primary, Hergovich, Alexander, primary, Cunnea, Paula, primary, Gabra, Hani, primary, Braicu, Elena Ioana, primary, Sehouli, Jalid, primary, Darb-Esfahani, Silvia, primary, Vanderstichele, Adriaan, primary, Vergote, Ignace, primary, Kreuzinger, Caroline, primary, Castillo-Tong, Dan Cacsire, primary, Wisman, G. Bea A., primary, Berns, Els MJJ, primary, Siddiqui, Nadeem, primary, Paul, James, primary, and Brown, Robert, primary

Published
2023
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15. Supplementary Table 4 from Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

Author

Flanagan, James M., primary, Wilson, Angela, primary, Koo, Chail, primary, Masrour, Nahal, primary, Gallon, John, primary, Loomis, Erick, primary, Flower, Kirsty, primary, Wilhelm-Benartzi, Charlotte, primary, Hergovich, Alexander, primary, Cunnea, Paula, primary, Gabra, Hani, primary, Braicu, Elena Ioana, primary, Sehouli, Jalid, primary, Darb-Esfahani, Silvia, primary, Vanderstichele, Adriaan, primary, Vergote, Ignace, primary, Kreuzinger, Caroline, primary, Castillo-Tong, Dan Cacsire, primary, Wisman, G. Bea A., primary, Berns, Els MJJ, primary, Siddiqui, Nadeem, primary, Paul, James, primary, and Brown, Robert, primary

Published
2023
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16. Supplementary Table 2 from Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

Author

Flanagan, James M., primary, Wilson, Angela, primary, Koo, Chail, primary, Masrour, Nahal, primary, Gallon, John, primary, Loomis, Erick, primary, Flower, Kirsty, primary, Wilhelm-Benartzi, Charlotte, primary, Hergovich, Alexander, primary, Cunnea, Paula, primary, Gabra, Hani, primary, Braicu, Elena Ioana, primary, Sehouli, Jalid, primary, Darb-Esfahani, Silvia, primary, Vanderstichele, Adriaan, primary, Vergote, Ignace, primary, Kreuzinger, Caroline, primary, Castillo-Tong, Dan Cacsire, primary, Wisman, G. Bea A., primary, Berns, Els MJJ, primary, Siddiqui, Nadeem, primary, Paul, James, primary, and Brown, Robert, primary

Published
2023
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17. Figure S6. sh-mediated RASSF1A depletion in HBEC-3 cells. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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18. HBEC-3 2D-migration induced by RASS1A-knockdown from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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19. Figure S1: Scheme of RASSF1 splicing isoforms and localization annealing regions of siRNAs and shRNAs used. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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20. Figure S3: Expression of siRNA-resistant RASSF1A rescues EMT phenotype induced by RASSF1A depletion. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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23. Data from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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24. Table S4 from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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25. Figure S8: RhoA activity is not influenced by RASSF1A depletion whereas constitutive activation of a Rho activity by Narciclasine still impairs RASSF1A-induced invasion. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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27. Figure S4: trans-endothelial invasion, enhanced-migration and growth in soft agar upon RASSF1A depletion in 4 transformed and untransformed epithelial bronchial cell lines. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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29. Figure S7: Time-course YAP cytoplasmic-nuclear shuttling upon RASSF1A depletion. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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30. Figure S2: Depletion of RASSF1A alone or with RASSF1C results in disappearance of tight junctions and decrease of adherens junction, replaced by diffuse adherent junctions. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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31. Figure S5. RASSF1A depletion reduces focal adhesion proteins and adhesion capacities in vitro. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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32. legends of supplemental figures from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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33. Figure S9: Loss of RhoB activity increases YAP nuclear localization. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Dubois, Fatéméh, primary, Keller, Maureen, primary, Calvayrac, Olivier, primary, Soncin, Fabrice, primary, Hoa, Lily, primary, Hergovich, Alexander, primary, Parrini, Maria-Carla, primary, Mazières, Julien, primary, Vaisse-Lesteven, Mélissa, primary, Camonis, Jacques, primary, Levallet, Guénaëlle, primary, and Zalcman, Gérard, primary

Published
2023
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35. Supplementary Figures S1-S11 from Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

Author

Robert Brown, James Paul, Nadeem Siddiqui, Els MJJ Berns, G. Bea A. Wisman, Dan Cacsire Castillo-Tong, Caroline Kreuzinger, Ignace Vergote, Adriaan Vanderstichele, Silvia Darb-Esfahani, Jalid Sehouli, Elena Ioana Braicu, Hani Gabra, Paula Cunnea, Alexander Hergovich, Charlotte Wilhelm-Benartzi, Kirsty Flower, Erick Loomis, John Gallon, Nahal Masrour, Chail Koo, Angela Wilson, and James M. Flanagan

Abstract

Supplementary Figure S1: Clinical Study Schematic. Supplementary Figure S2: Significant changes in blood DNA methylation at time of ovarian cancer relapse compared to at presentation. Supplementary Figure S3: Methylation profiles of blood DNA at time of ovarian cancer relapse predict overall survival. Supplementary Figure S4: Pyrosequencing Validation of blood DNA at time of ovarian cancer relapse predict overall survival. Supplementary Figure S5. Methylation profile validation of tumour DNA at time of ovarian cancer relapse predicts overall survival. Supplementary Figure S6: Deriving clusters using methylation levels of these 8 probes in blood DNA at the time of presentation neither predicts time to first progression nor overall survival. Supplementary Figure S7. Clonal variation in MLH1- and MLH1+ cell lines. Supplementary Figure S8. Cisplatin treatment and long term growth does not affect cisplatin sensitivity of MLH1+ or MLH1- clones. Supplementary Figure S9. Bisulphite pyrosequencing validates five CpG sites. Supplementary Figure S10. Dinucleotide enrichment analysis. Supplementary Figure S11. Mechanism for platinum-induced methylation changes in MLH1-deficient and -proficient cells.

Published
2023

36. Data from Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

Author

Robert Brown, James Paul, Nadeem Siddiqui, Els MJJ Berns, G. Bea A. Wisman, Dan Cacsire Castillo-Tong, Caroline Kreuzinger, Ignace Vergote, Adriaan Vanderstichele, Silvia Darb-Esfahani, Jalid Sehouli, Elena Ioana Braicu, Hani Gabra, Paula Cunnea, Alexander Hergovich, Charlotte Wilhelm-Benartzi, Kirsty Flower, Erick Loomis, John Gallon, Nahal Masrour, Chail Koo, Angela Wilson, and James M. Flanagan

Abstract

Purpose: DNA damage repair can lead to epigenetic changes. DNA mismatch repair proteins bind to platinum DNA adducts and at sites of DNA damage can recruit the DNA methylating enzyme DNMT1, resulting in aberrant methylation. We hypothesised that DNA damage repair during platinum-based chemotherapy may cause aberrant DNA methylation in normal tissues of patients such as blood.Experimental Design: We used Illumina 450k methylation arrays and bisulphite pyrosequencing to investigate methylation at presentation and relapse in blood DNA from patients with ovarian cancer enrolled in the SCOTROC1 trial (n = 247) and in a cohort of ovarian tumor DNA samples collected at first relapse (n = 46). We used an ovarian cancer cell line model to investigate the role of the DNA mismatch repair gene MLH1 in platinum-induced methylation changes.Results: Specific CpG methylation changes in blood at relapse are observed following platinum-based chemotherapy and are associated with patient survival, independent of other clinical factors [hazard ratio, 3.7; 95% confidence interval, 1.8–7.6, P = 2.8 × 10−4]. Similar changes occur in ovarian tumors at relapse, also associated with patient survival (hazard ratio, 2.6; 95% confidence interval, 1.0–6.8, P = 0.048). Using an ovarian cancer cell line model, we demonstrate that functional mismatch repair increases the frequency of platinum-induced methylation.Conclusions: DNA methylation in blood at relapse following chemotherapy, and not at presentation, is informative regarding survival of patients with ovarian cancer. Functional DNA mismatch repair increases the frequency of DNA methylation changes induced by platinum. DNA methylation in blood following chemotherapy could provide a noninvasive means of monitoring patients' epigenetic responses to treatment without requiring a tumor biopsy. Clin Cancer Res; 23(9); 2213–22. ©2016 AACR.

Published
2023

37. Supplementary Table 4 from Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

Author

Robert Brown, James Paul, Nadeem Siddiqui, Els MJJ Berns, G. Bea A. Wisman, Dan Cacsire Castillo-Tong, Caroline Kreuzinger, Ignace Vergote, Adriaan Vanderstichele, Silvia Darb-Esfahani, Jalid Sehouli, Elena Ioana Braicu, Hani Gabra, Paula Cunnea, Alexander Hergovich, Charlotte Wilhelm-Benartzi, Kirsty Flower, Erick Loomis, John Gallon, Nahal Masrour, Chail Koo, Angela Wilson, and James M. Flanagan

Abstract

Supplementary Table S4 - Summary Statistics for 8 CpG sites and Annotation

Published
2023

38. Supplementary Table 3 from Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

Author

Robert Brown, James Paul, Nadeem Siddiqui, Els MJJ Berns, G. Bea A. Wisman, Dan Cacsire Castillo-Tong, Caroline Kreuzinger, Ignace Vergote, Adriaan Vanderstichele, Silvia Darb-Esfahani, Jalid Sehouli, Elena Ioana Braicu, Hani Gabra, Paula Cunnea, Alexander Hergovich, Charlotte Wilhelm-Benartzi, Kirsty Flower, Erick Loomis, John Gallon, Nahal Masrour, Chail Koo, Angela Wilson, and James M. Flanagan

Abstract

Supplementary Table S3 - Cox Proportional Hazards Regression models

Published
2023

39. Supplementary Table 1 from Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

Author

Robert Brown, James Paul, Nadeem Siddiqui, Els MJJ Berns, G. Bea A. Wisman, Dan Cacsire Castillo-Tong, Caroline Kreuzinger, Ignace Vergote, Adriaan Vanderstichele, Silvia Darb-Esfahani, Jalid Sehouli, Elena Ioana Braicu, Hani Gabra, Paula Cunnea, Alexander Hergovich, Charlotte Wilhelm-Benartzi, Kirsty Flower, Erick Loomis, John Gallon, Nahal Masrour, Chail Koo, Angela Wilson, and James M. Flanagan

Abstract

Supplementary Table S1 - Patient Characteristics

Published
2023

40. Supplementary Table 2 from Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

Author

Robert Brown, James Paul, Nadeem Siddiqui, Els MJJ Berns, G. Bea A. Wisman, Dan Cacsire Castillo-Tong, Caroline Kreuzinger, Ignace Vergote, Adriaan Vanderstichele, Silvia Darb-Esfahani, Jalid Sehouli, Elena Ioana Braicu, Hani Gabra, Paula Cunnea, Alexander Hergovich, Charlotte Wilhelm-Benartzi, Kirsty Flower, Erick Loomis, John Gallon, Nahal Masrour, Chail Koo, Angela Wilson, and James M. Flanagan

Abstract

Supplementary Table S2 - Pyrosequencing Primers used in this study

Published
2023

41. Figure S6. sh-mediated RASSF1A depletion in HBEC-3 cells. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Gérard Zalcman, Guénaëlle Levallet, Jacques Camonis, Mélissa Vaisse-Lesteven, Julien Mazières, Maria-Carla Parrini, Alexander Hergovich, Lily Hoa, Fabrice Soncin, Olivier Calvayrac, Maureen Keller, and Fatéméh Dubois

Abstract

HBEC-3 cells were transfected with non-silencing shRNA (Control), shRASSF1A-777 and shRASSF1A-779. A) Changes in RASSF1A and Yap expression assessed by immunofluorescence (Red=RASSF1A, Green=Yap, Blue=DAPI) experiments. Scale bar represents 50 µm. B) The migration speed (µm/h) of transfected cells was determined by wound assay on collagen IV. Mitomycin C (1 µg/ml) was added to medium 12h before wounding. The invasion capacity was assessed using a BioCoat Matrigel Invasion Chamber. The relative invasion was normalized to that of the cells transfected with Control. C) Representative images of colony formation of transfected cells in soft agar. Scale bar represents 20 µm. For all of the histograms, error bars indicate the standard error of the mean (SEM) of at least three independent experiments. *p

Published
2023

42. HBEC-3 2D-migration induced by RASS1A-knockdown from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Gérard Zalcman, Guénaëlle Levallet, Jacques Camonis, Mélissa Vaisse-Lesteven, Julien Mazières, Maria-Carla Parrini, Alexander Hergovich, Lily Hoa, Fabrice Soncin, Olivier Calvayrac, Maureen Keller, and Fatéméh Dubois

Abstract

HBEC-3 2D-migration induced by RASS1A-knockdown showed features evoking both collective migration and multicellular streaming

Published
2023

45. Figure S4: trans-endothelial invasion, enhanced-migration and growth in soft agar upon RASSF1A depletion in 4 transformed and untransformed epithelial bronchial cell lines. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Gérard Zalcman, Guénaëlle Levallet, Jacques Camonis, Mélissa Vaisse-Lesteven, Julien Mazières, Maria-Carla Parrini, Alexander Hergovich, Lily Hoa, Fabrice Soncin, Olivier Calvayrac, Maureen Keller, and Fatéméh Dubois

Abstract

The cells were transiently transfected with siNeg, siRASSF1A or siRASSF1AC. The experiences were performed 48 hours after transfection A. The trans-endothelial invasion capacity of transfected cells was assessed using a cell culture insert (BioCoat Matrigel Invasion Chamber) on which a monolayer of endothelial cells has been grown previously. The total number of cells that invaded to the lower side of the filter after 48h was counted under the microscope (10X). The relative invasion was normalized to that of the cells transfected with siNeg. B. The migration speed (µm/h) of transfected HBEC-3 RasV12, H1975 and BEAS-2B cells was determined by wound healing assay on Fibronectin (HBEC-3) or collagen IV (H1975 and BEAS-2B). Mitomycin C (1 µg/ml) was added to medium 12h before wounding. C. The invasion capacity of transfected HBEC-3RasV12, H1975, BEAS-2B, BEAS-2B RasV12 cells was assessed using BioCoat Matrigel Invasion Chambers. The total number of cells that invaded to the lower side of the filter after 48h was counted under the microscope (10X). The relative invasion was normalized to that of the cells transfected with siNeg. D. The capacity of growth without adherence in soft agar of HBEC-3 RasV12 and BEAS-2B cells transfected by an inactive siRNA or SiRASSF1A was evaluated by quantification of colony formation. The number of colonies was scored after 7 days. One representative experiment is shown in a right panel. Scale bar represents 80 µm. For all of the histograms, error bars indicate the standard error of the mean (SEM) of at least three independent experiments. For all of the histograms, error bars indicate the standard error of the mean (SEM) of at least three independent experiments. *p

Published
2023

46. Figure S2: Depletion of RASSF1A alone or with RASSF1C results in disappearance of tight junctions and decrease of adherens junction, replaced by diffuse adherent junctions. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Gérard Zalcman, Guénaëlle Levallet, Jacques Camonis, Mélissa Vaisse-Lesteven, Julien Mazières, Maria-Carla Parrini, Alexander Hergovich, Lily Hoa, Fabrice Soncin, Olivier Calvayrac, Maureen Keller, and Fatéméh Dubois

Abstract

Three independent air-liquid cultures, each requiring 21 days of growth before fixation and observation, were analyzed. For each culture, 2 slides through the porous membrane and the cells have been performed, those slides being processed at the center of the membrane to avoid artifacts linked to a peripheral location. For siNeg condition (only one stratum of cells) 50 to 70 cells were observed, whereas for siRASSF1A conditions, 50 to 250 cells (several strata of cells) were analyzed. For all of the histograms, error bars indicate the standard error of the mean (SEM) of at least three independent experiments. *p

Published
2023

47. Figure S5. RASSF1A depletion reduces focal adhesion proteins and adhesion capacities in vitro. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Gérard Zalcman, Guénaëlle Levallet, Jacques Camonis, Mélissa Vaisse-Lesteven, Julien Mazières, Maria-Carla Parrini, Alexander Hergovich, Lily Hoa, Fabrice Soncin, Olivier Calvayrac, Maureen Keller, and Fatéméh Dubois

Abstract

The HBEC-3 cells were transiently transfected with siNeg, si RASSF1A or siRASSF1AC. The experiences were performed 48 hours after transfection. A. Expression of focal adhesion complex proteins was examined by RT-PCR analysis. B & C. Adhesion strength of the HBEC-3 cells on fibronectin (B) and laminin (C). For all of the histograms, error bars indicate the standard error of the mean (SEM) of at least three independent experiments. *p

Published
2023

49. Figure S3: Expression of siRNA-resistant RASSF1A rescues EMT phenotype induced by RASSF1A depletion. from RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

Author

Gérard Zalcman, Guénaëlle Levallet, Jacques Camonis, Mélissa Vaisse-Lesteven, Julien Mazières, Maria-Carla Parrini, Alexander Hergovich, Lily Hoa, Fabrice Soncin, Olivier Calvayrac, Maureen Keller, and Fatéméh Dubois

Abstract

HBEC-3 cells were transiently transfected with siNeg or siRASSF1A in association with either pcDNA3-RASSF1A or pcDNA3-RASSF1C. The experiences were performed 48 hours after transfection. A. Representative images for RASSF1A expression changes by immunofluorescence and confocal microscopy. RASSF1A primary antibody (Red) followed by Alexa 555 conjugated secondary antibody along with DAPI for DNA (Blue) was used as a control along with DAPI for DNA (Blue). Scale bar represents 50 µm. B. Representative blots for quantification of Twist and Vimentin proteins levels by western blotting in HBEC-3 cells. Actin was used as an internal control. (n=2) C. The migration speed (µm/h) of transfected HBEC-3 cells was determined by wound healing assay on collagen I & IV. Mitomycin C (1 µg/ml) was added to medium 12h before scratch in order to limit cell proliferation. D. Representative images for nuclear localization of Yap in HBEC-3 cell by immunofluorescence and confocal microscopy. The cells stained by Yap primary antibody (Green) followed by Alexa488 conjugated secondary antibody, along with DAPI for DNA (Blue). Scale bar represents 50 µm. For all of the histograms, error bars indicate the standard error of the mean (SEM) of at least three independent experiments. *p

Published
2023

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