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1. Glioma subtype classification from histopathological images using in-domain and out-of-domain transfer learning: An experimental study

Author

Despotovic, Vladimir, Kim, Sang-Yoon, Hau, Ann-Christin, Kakoichankava, Aliaksandra, Klamminger, Gilbert Georg, Borgmann, Felix Bruno Kleine, Frauenknecht, Katrin B. M., Mittelbronn, Michel, and Nazarov, Petr V.

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

We provide in this paper a comprehensive comparison of various transfer learning strategies and deep learning architectures for computer-aided classification of adult-type diffuse gliomas. We evaluate the generalizability of out-of-domain ImageNet representations for a target domain of histopathological images, and study the impact of in-domain adaptation using self-supervised and multi-task learning approaches for pretraining the models using the medium-to-large scale datasets of histopathological images. A semi-supervised learning approach is furthermore proposed, where the fine-tuned models are utilized to predict the labels of unannotated regions of the whole slide images (WSI). The models are subsequently retrained using the ground-truth labels and weak labels determined in the previous step, providing superior performance in comparison to standard in-domain transfer learning with balanced accuracy of 96.91% and F1-score 97.07%, and minimizing the pathologist's efforts for annotation. Finally, we provide a visualization tool working at WSI level which generates heatmaps that highlight tumor areas; thus, providing insights to pathologists concerning the most informative parts of the WSI.

Published
2023
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2. Federated Learning Enables Big Data for Rare Cancer Boundary Detection

Author

Pati, Sarthak, Baid, Ujjwal, Edwards, Brandon, Sheller, Micah, Wang, Shih-Han, Reina, G Anthony, Foley, Patrick, Gruzdev, Alexey, Karkada, Deepthi, Davatzikos, Christos, Sako, Chiharu, Ghodasara, Satyam, Bilello, Michel, Mohan, Suyash, Vollmuth, Philipp, Brugnara, Gianluca, Preetha, Chandrakanth J, Sahm, Felix, Maier-Hein, Klaus, Zenk, Maximilian, Bendszus, Martin, Wick, Wolfgang, Calabrese, Evan, Rudie, Jeffrey, Villanueva-Meyer, Javier, Cha, Soonmee, Ingalhalikar, Madhura, Jadhav, Manali, Pandey, Umang, Saini, Jitender, Garrett, John, Larson, Matthew, Jeraj, Robert, Currie, Stuart, Frood, Russell, Fatania, Kavi, Huang, Raymond Y, Chang, Ken, Balana, Carmen, Capellades, Jaume, Puig, Josep, Trenkler, Johannes, Pichler, Josef, Necker, Georg, Haunschmidt, Andreas, Meckel, Stephan, Shukla, Gaurav, Liem, Spencer, Alexander, Gregory S, Lombardo, Joseph, Palmer, Joshua D, Flanders, Adam E, Dicker, Adam P, Sair, Haris I, Jones, Craig K, Venkataraman, Archana, Jiang, Meirui, So, Tiffany Y, Chen, Cheng, Heng, Pheng Ann, Dou, Qi, Kozubek, Michal, Lux, Filip, Michálek, Jan, Matula, Petr, Keřkovský, Miloš, Kopřivová, Tereza, Dostál, Marek, Vybíhal, Václav, Vogelbaum, Michael A, Mitchell, J Ross, Farinhas, Joaquim, Maldjian, Joseph A, Yogananda, Chandan Ganesh Bangalore, Pinho, Marco C, Reddy, Divya, Holcomb, James, Wagner, Benjamin C, Ellingson, Benjamin M, Cloughesy, Timothy F, Raymond, Catalina, Oughourlian, Talia, Hagiwara, Akifumi, Wang, Chencai, To, Minh-Son, Bhardwaj, Sargam, Chong, Chee, Agzarian, Marc, Falcão, Alexandre Xavier, Martins, Samuel B, Teixeira, Bernardo C A, Sprenger, Flávia, Menotti, David, Lucio, Diego R, LaMontagne, Pamela, Marcus, Daniel, Wiestler, Benedikt, Kofler, Florian, Ezhov, Ivan, Metz, Marie, Jain, Rajan, Lee, Matthew, Lui, Yvonne W, McKinley, Richard, Slotboom, Johannes, Radojewski, Piotr, Meier, Raphael, Wiest, Roland, Murcia, Derrick, Fu, Eric, Haas, Rourke, Thompson, John, Ormond, David Ryan, Badve, Chaitra, Sloan, Andrew E, Vadmal, Vachan, Waite, Kristin, Colen, Rivka R, Pei, Linmin, Ak, Murat, Srinivasan, Ashok, Bapuraj, J Rajiv, Rao, Arvind, Wang, Nicholas, Yoshiaki, Ota, Moritani, Toshio, Turk, Sevcan, Lee, Joonsang, Prabhudesai, Snehal, Morón, Fanny, Mandel, Jacob, Kamnitsas, Konstantinos, Glocker, Ben, Dixon, Luke V M, Williams, Matthew, Zampakis, Peter, Panagiotopoulos, Vasileios, Tsiganos, Panagiotis, Alexiou, Sotiris, Haliassos, Ilias, Zacharaki, Evangelia I, Moustakas, Konstantinos, Kalogeropoulou, Christina, Kardamakis, Dimitrios M, Choi, Yoon Seong, Lee, Seung-Koo, Chang, Jong Hee, Ahn, Sung Soo, Luo, Bing, Poisson, Laila, Wen, Ning, Tiwari, Pallavi, Verma, Ruchika, Bareja, Rohan, Yadav, Ipsa, Chen, Jonathan, Kumar, Neeraj, Smits, Marion, van der Voort, Sebastian R, Alafandi, Ahmed, Incekara, Fatih, Wijnenga, Maarten MJ, Kapsas, Georgios, Gahrmann, Renske, Schouten, Joost W, Dubbink, Hendrikus J, Vincent, Arnaud JPE, Bent, Martin J van den, French, Pim J, Klein, Stefan, Yuan, Yading, Sharma, Sonam, Tseng, Tzu-Chi, Adabi, Saba, Niclou, Simone P, Keunen, Olivier, Hau, Ann-Christin, Vallières, Martin, Fortin, David, Lepage, Martin, Landman, Bennett, Ramadass, Karthik, Xu, Kaiwen, Chotai, Silky, Chambless, Lola B, Mistry, Akshitkumar, Thompson, Reid C, Gusev, Yuriy, Bhuvaneshwar, Krithika, Sayah, Anousheh, Bencheqroun, Camelia, Belouali, Anas, Madhavan, Subha, Booth, Thomas C, Chelliah, Alysha, Modat, Marc, Shuaib, Haris, Dragos, Carmen, Abayazeed, Aly, Kolodziej, Kenneth, Hill, Michael, Abbassy, Ahmed, Gamal, Shady, Mekhaimar, Mahmoud, Qayati, Mohamed, Reyes, Mauricio, Park, Ji Eun, Yun, Jihye, Kim, Ho Sung, Mahajan, Abhishek, Muzi, Mark, Benson, Sean, Beets-Tan, Regina G H, Teuwen, Jonas, Herrera-Trujillo, Alejandro, Trujillo, Maria, Escobar, William, Abello, Ana, Bernal, Jose, Gómez, Jhon, Choi, Joseph, Baek, Stephen, Kim, Yusung, Ismael, Heba, Allen, Bryan, Buatti, John M, Kotrotsou, Aikaterini, Li, Hongwei, Weiss, Tobias, Weller, Michael, Bink, Andrea, Pouymayou, Bertrand, Shaykh, Hassan F, Saltz, Joel, Prasanna, Prateek, Shrestha, Sampurna, Mani, Kartik M, Payne, David, Kurc, Tahsin, Pelaez, Enrique, Franco-Maldonado, Heydy, Loayza, Francis, Quevedo, Sebastian, Guevara, Pamela, Torche, Esteban, Mendoza, Cristobal, Vera, Franco, Ríos, Elvis, López, Eduardo, Velastin, Sergio A, Ogbole, Godwin, Oyekunle, Dotun, Odafe-Oyibotha, Olubunmi, Osobu, Babatunde, Shu'aibu, Mustapha, Dorcas, Adeleye, Soneye, Mayowa, Dako, Farouk, Simpson, Amber L, Hamghalam, Mohammad, Peoples, Jacob J, Hu, Ricky, Tran, Anh, Cutler, Danielle, Moraes, Fabio Y, Boss, Michael A, Gimpel, James, Veettil, Deepak Kattil, Schmidt, Kendall, Bialecki, Brian, Marella, Sailaja, Price, Cynthia, Cimino, Lisa, Apgar, Charles, Shah, Prashant, Menze, Bjoern, Barnholtz-Sloan, Jill S, Martin, Jason, and Bakas, Spyridon

Subjects
Computer Science - Machine Learning, Electrical Engineering and Systems Science - Image and Video Processing
Abstract

Although machine learning (ML) has shown promise in numerous domains, there are concerns about generalizability to out-of-sample data. This is currently addressed by centrally sharing ample, and importantly diverse, data from multiple sites. However, such centralization is challenging to scale (or even not feasible) due to various limitations. Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here we present findings from the largest FL study to-date, involving data from 71 healthcare institutions across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, utilizing the largest dataset of such patients ever used in the literature (25,256 MRI scans from 6,314 patients). We demonstrate a 33% improvement over a publicly trained model to delineate the surgically targetable tumor, and 23% improvement over the tumor's entire extent. We anticipate our study to: 1) enable more studies in healthcare informed by large and diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further quantitative analyses for glioblastoma via performance optimization of our consensus model for eventual public release, and 3) demonstrate the effectiveness of FL at such scale and task complexity as a paradigm shift for multi-site collaborations, alleviating the need for data sharing., Comment: federated learning, deep learning, convolutional neural network, segmentation, brain tumor, glioma, glioblastoma, FeTS, BraTS

Published
2022
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3. Author Correction: Federated learning enables big data for rare cancer boundary detection

Author

Pati, Sarthak, Baid, Ujjwal, Edwards, Brandon, Sheller, Micah, Wang, Shih-Han, Reina, G. Anthony, Foley, Patrick, Gruzdev, Alexey, Karkada, Deepthi, Davatzikos, Christos, Sako, Chiharu, Ghodasara, Satyam, Bilello, Michel, Mohan, Suyash, Vollmuth, Philipp, Brugnara, Gianluca, Preetha, Chandrakanth J., Sahm, Felix, Maier-Hein, Klaus, Zenk, Maximilian, Bendszus, Martin, Wick, Wolfgang, Calabrese, Evan, Rudie, Jeffrey, Villanueva-Meyer, Javier, Cha, Soonmee, Ingalhalikar, Madhura, Jadhav, Manali, Pandey, Umang, Saini, Jitender, Garrett, John, Larson, Matthew, Jeraj, Robert, Currie, Stuart, Frood, Russell, Fatania, Kavi, Huang, Raymond Y., Chang, Ken, Balaña, Carmen, Capellades, Jaume, Puig, Josep, Trenkler, Johannes, Pichler, Josef, Necker, Georg, Haunschmidt, Andreas, Meckel, Stephan, Shukla, Gaurav, Liem, Spencer, Alexander, Gregory S., Lombardo, Joseph, Palmer, Joshua D., Flanders, Adam E., Dicker, Adam P., Sair, Haris I., Jones, Craig K., Venkataraman, Archana, Jiang, Meirui, So, Tiffany Y., Chen, Cheng, Heng, Pheng Ann, Dou, Qi, Kozubek, Michal, Lux, Filip, Michálek, Jan, Matula, Petr, Keřkovský, Miloš, Kopřivová, Tereza, Dostál, Marek, Vybíhal, Václav, Vogelbaum, Michael A., Mitchell, J. Ross, Farinhas, Joaquim, Maldjian, Joseph A., Yogananda, Chandan Ganesh Bangalore, Pinho, Marco C., Reddy, Divya, Holcomb, James, Wagner, Benjamin C., Ellingson, Benjamin M., Cloughesy, Timothy F., Raymond, Catalina, Oughourlian, Talia, Hagiwara, Akifumi, Wang, Chencai, To, Minh-Son, Bhardwaj, Sargam, Chong, Chee, Agzarian, Marc, Falcão, Alexandre Xavier, Martins, Samuel B., Teixeira, Bernardo C. A., Sprenger, Flávia, Menotti, David, Lucio, Diego R., LaMontagne, Pamela, Marcus, Daniel, Wiestler, Benedikt, Kofler, Florian, Ezhov, Ivan, Metz, Marie, Jain, Rajan, Lee, Matthew, Lui, Yvonne W., McKinley, Richard, Slotboom, Johannes, Radojewski, Piotr, Meier, Raphael, Wiest, Roland, Murcia, Derrick, Fu, Eric, Haas, Rourke, Thompson, John, Ormond, David Ryan, Badve, Chaitra, Sloan, Andrew E., Vadmal, Vachan, Waite, Kristin, Colen, Rivka R., Pei, Linmin, Ak, Murat, Srinivasan, Ashok, Bapuraj, J. Rajiv, Rao, Arvind, Wang, Nicholas, Yoshiaki, Ota, Moritani, Toshio, Turk, Sevcan, Lee, Joonsang, Prabhudesai, Snehal, Morón, Fanny, Mandel, Jacob, Kamnitsas, Konstantinos, Glocker, Ben, Dixon, Luke V. M., Williams, Matthew, Zampakis, Peter, Panagiotopoulos, Vasileios, Tsiganos, Panagiotis, Alexiou, Sotiris, Haliassos, Ilias, Zacharaki, Evangelia I., Moustakas, Konstantinos, Kalogeropoulou, Christina, Kardamakis, Dimitrios M., Choi, Yoon Seong, Lee, Seung-Koo, Chang, Jong Hee, Ahn, Sung Soo, Luo, Bing, Poisson, Laila, Wen, Ning, Tiwari, Pallavi, Verma, Ruchika, Bareja, Rohan, Yadav, Ipsa, Chen, Jonathan, Kumar, Neeraj, Smits, Marion, van der Voort, Sebastian R., Alafandi, Ahmed, Incekara, Fatih, Wijnenga, Maarten M. J., Kapsas, Georgios, Gahrmann, Renske, Schouten, Joost W., Dubbink, Hendrikus J., Vincent, Arnaud J. P. E., van den Bent, Martin J., French, Pim J., Klein, Stefan, Yuan, Yading, Sharma, Sonam, Tseng, Tzu-Chi, Adabi, Saba, Niclou, Simone P., Keunen, Olivier, Hau, Ann-Christin, Vallières, Martin, Fortin, David, Lepage, Martin, Landman, Bennett, Ramadass, Karthik, Xu, Kaiwen, Chotai, Silky, Chambless, Lola B., Mistry, Akshitkumar, Thompson, Reid C., Gusev, Yuriy, Bhuvaneshwar, Krithika, Sayah, Anousheh, Bencheqroun, Camelia, Belouali, Anas, Madhavan, Subha, Booth, Thomas C., Chelliah, Alysha, Modat, Marc, Shuaib, Haris, Dragos, Carmen, Abayazeed, Aly, Kolodziej, Kenneth, Hill, Michael, Abbassy, Ahmed, Gamal, Shady, Mekhaimar, Mahmoud, Qayati, Mohamed, Reyes, Mauricio, Park, Ji Eun, Yun, Jihye, Kim, Ho Sung, Mahajan, Abhishek, Muzi, Mark, Benson, Sean, Beets-Tan, Regina G. H., Teuwen, Jonas, Herrera-Trujillo, Alejandro, Trujillo, Maria, Escobar, William, Abello, Ana, Bernal, Jose, Gómez, Jhon, Choi, Joseph, Baek, Stephen, Kim, Yusung, Ismael, Heba, Allen, Bryan, Buatti, John M., Kotrotsou, Aikaterini, Li, Hongwei, Weiss, Tobias, Weller, Michael, Bink, Andrea, Pouymayou, Bertrand, Shaykh, Hassan F., Saltz, Joel, Prasanna, Prateek, Shrestha, Sampurna, Mani, Kartik M., Payne, David, Kurc, Tahsin, Pelaez, Enrique, Franco-Maldonado, Heydy, Loayza, Francis, Quevedo, Sebastian, Guevara, Pamela, Torche, Esteban, Mendoza, Cristobal, Vera, Franco, Ríos, Elvis, López, Eduardo, Velastin, Sergio A., Ogbole, Godwin, Soneye, Mayowa, Oyekunle, Dotun, Odafe-Oyibotha, Olubunmi, Osobu, Babatunde, Shu’aibu, Mustapha, Dorcas, Adeleye, Dako, Farouk, Simpson, Amber L., Hamghalam, Mohammad, Peoples, Jacob J., Hu, Ricky, Tran, Anh, Cutler, Danielle, Moraes, Fabio Y., Boss, Michael A., Gimpel, James, Veettil, Deepak Kattil, Schmidt, Kendall, Bialecki, Brian, Marella, Sailaja, Price, Cynthia, Cimino, Lisa, Apgar, Charles, Shah, Prashant, Menze, Bjoern, Barnholtz-Sloan, Jill S., Martin, Jason, and Bakas, Spyridon

Published
2023
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5. Glioma through the looking GLASS: molecular evolution of diffuse gliomas and the Glioma Longitudinal Analysis Consortium

Author

Aldape, Kenneth, Amin, Samirkumar B, Ashley, David M, Barnholtz-Sloan, Jill S, Bates, Amanda J, Beroukhim, Rameen, Bock, Christoph, Brat, Daniel J, Claus, Elizabeth B, Costello, Joseph F, de Groot, John F, Finocchiaro, Gaetano, French, Pim J, Gan, Hui K, Griffith, Brent, Herold-Mende, Christel C, Horbinski, Craig, Iavarone, Antonio, Kalkanis, Steven N, Karabatsou, Konstantina, Kim, Hoon, Kouwenhoven, Mathilde CM, McDonald, Kerrie L, Miletic, Hrvoje, Nam, Do-Hyun, Ng, Ho Keung, Niclou, Simone P, Noushmehr, Houtan, Ormond, D Ryan, Poisson, Laila M, Reifenberger, Guido, Roncaroli, Federico, Sa, Jason K, Smitt, Peter AE Sillevis, Smits, Marion, Souza, Camila F, Tabatabai, Ghazaleh, Van Meir, Erwin G, Verhaak, Roel GW, Watts, Colin, Wesseling, Pieter, Woehrer, Adelheid, Yung, WK Alfred, Jungk, Christine, Hau, Ann-Christin, van Dyck, Eric, Westerman, Bart A, Yin, Julia, Abiola, Olajide, Zeps, Nikolaj, Grimmond, Sean, Buckland, Michael, Khasraw, Mustafa, Sulman, Erik P, Muscat, Andrea M, and Stead, Lucy

Subjects
Cancer, Human Genome, Brain Cancer, Rare Diseases, Orphan Drug, Brain Disorders, Neurosciences, Genetics, Brain Neoplasms, Evolution, Molecular, Genomics, Glioma, Humans, Longitudinal Studies, characterization, evolution, glioma, sequencing, subtypes, GLASS Consortium, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal Analysis Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities and, ultimately, improved outcomes for a patient population in need.

Published
2018

6. Table S1 from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author

Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary

Published
2024
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7. Supp Figures from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author

Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary

Published
2024
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8. Supplemental Figures Legends from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author

Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary

Published
2024
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9. Data from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author

Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary

Published
2024
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10. Supplementary Appendix from The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author

Malta, Tathiane M., primary, Sabedot, Thais S., primary, Morosini, Natalia S., primary, Datta, Indrani, primary, Garofano, Luciano, primary, Vallentgoed, Wies, primary, Varn, Frederick S., primary, Aldape, Kenneth, primary, D'Angelo, Fulvio, primary, Bakas, Spyridon, primary, Barnholtz-Sloan, Jill S., primary, Gan, Hui K., primary, Hasanain, Mohammad, primary, Hau, Ann-Christin, primary, Johnson, Kevin C., primary, Cazacu, Simona, primary, deCarvalho, Ana C., primary, Khasraw, Mustafa, primary, Kocakavuk, Emre, primary, Kouwenhoven, Mathilde C.M., primary, Migliozzi, Simona, primary, Niclou, Simone P., primary, Niers, Johanna M., primary, Ormond, D. Ryan, primary, Paek, Sun Ha, primary, Reifenberger, Guido, primary, Sillevis Smitt, Peter A., primary, Smits, Marion, primary, Stead, Lucy F., primary, van den Bent, Martin J., primary, Van Meir, Erwin G., primary, Walenkamp, Annemiek, primary, Weiss, Tobias, primary, Weller, Michael, primary, Westerman, Bart A., primary, Ylstra, Bauke, primary, Wesseling, Pieter, primary, Lasorella, Anna, primary, French, Pim J., primary, Poisson, Laila M., primary, Woehrer, Adelheid, primary, Lowman, Allison K, primary, deCarvalho, Ana C, primary, Castro, Ana Valeria, primary, Transou, Andrea, primary, Brodbelt, Andrew R, primary, Golebiewska, Anna, primary, Molinaro, Annette M, primary, Iavarone, Antonio, primary, Ismail, Azzam, primary, Westerman, Bart A, primary, Bock, Christoph, primary, Brat, Daniel J, primary, Van Meir, Erwin G, primary, Barthel, Floris P, primary, Varn, Frederick S, primary, Finocchiaro, Gaetano, primary, Rao, Ganesh, primary, Zadeh, Gelareh, primary, ngNg, Ho Keu, primary, Kim, Hoon, primary, Noushmehr, Houtan, primary, Miletic, Hrvoje, primary, Gan, Hui K, primary, Rock, Jack, primary, Snyder, James M, primary, Huse, Jason T, primary, Connelly, Jennifer M, primary, Barnholtz-Sloan, Jill S, primary, Niers, Johanna M, primary, deGroot, John F, primary, Akdemir, Kadir C, primary, Kannan, Kasthuri S, primary, Ligon, Keith L, primary, Bulsara, Ketan R, primary, Johnson, Kevin C, primary, Alfaro, Kristin D, primary, Poisson, Laila M, primary, Stead, Lucy F, primary, Nasrallah, MacLean P, primary, van den Bent, Martin J, primary, Kouwenhoven, Mathilde CM, primary, Gould, Peter V, primary, Smitt, Peter A Sillevis, primary, LaViolette, Peter S, primary, Tatman, Philip D, primary, French, Pim J, primary, Beroukhim, Rameen, primary, Verhaak, Roel G.W., primary, Niclou, Simone P, primary, Kalkanis, Steven, primary, Short, Susan C, primary, Ghazaleh, Tabatabai, primary, Malta, Tathiane M, primary, Sabedot, Thais S, primary, Walbert, Tobias, primary, Baid, Ujjwal, primary, and Yung, W. K. Alfred, primary

Published
2024
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12. The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen

Author

Malta, Tathiane M; https://orcid.org/0000-0003-1129-5791, Sabedot, Thais S; https://orcid.org/0000-0002-7813-483X, Morosini, Natalia S; https://orcid.org/0000-0002-9294-9461, Datta, Indrani; https://orcid.org/0000-0001-7548-9881, Garofano, Luciano; https://orcid.org/0000-0001-8582-0865, Vallentgoed, Wies R; https://orcid.org/0000-0001-6373-7710, Varn, Frederick S; https://orcid.org/0000-0001-6307-016X, Aldape, Kenneth; https://orcid.org/0000-0001-5119-7550, D'Angelo, Fulvio; https://orcid.org/0000-0002-4940-4693, Bakas, Spyridon; https://orcid.org/0000-0001-8734-6482, Barnholtz-Sloan, Jill S; https://orcid.org/0000-0001-6190-9304, Gan, Hui K; https://orcid.org/0000-0001-7319-8546, Hasanain, Mohammad; https://orcid.org/0000-0001-5207-101X, Hau, Ann-Christin; https://orcid.org/0000-0002-4412-2355, Johnson, Kevin C; https://orcid.org/0000-0003-0016-5158, Cazacu, Simona; https://orcid.org/0000-0002-6085-4177, deCarvalho, Ana C; https://orcid.org/0000-0003-1183-4548, Khasraw, Mustafa; https://orcid.org/0000-0003-3249-9849, Kocakavuk, Emre; https://orcid.org/0000-0003-1920-0494, Kouwenhoven, Mathilde C M; https://orcid.org/0000-0001-5252-4365, Migliozzi, Simona; https://orcid.org/0000-0002-4870-8943, Niclou, Simone P; https://orcid.org/0000-0002-3417-9534, Niers, Johanna M; https://orcid.org/0000-0002-0366-8247, Ormond, D Ryan; https://orcid.org/0000-0001-7027-2915, Paek, Sun Ha; https://orcid.org/0000-0003-3007-8653, Reifenberger, Guido; https://orcid.org/0000-0002-1419-9837, Sillevis Smitt, Peter A; https://orcid.org/0000-0001-8044-6798, Smits, Marion; https://orcid.org/0000-0001-5563-2871, Weiss, Tobias; https://orcid.org/0000-0002-5533-9429, Weller, Michael; https://orcid.org/0000-0002-1748-174X, et al, Malta, Tathiane M; https://orcid.org/0000-0003-1129-5791, Sabedot, Thais S; https://orcid.org/0000-0002-7813-483X, Morosini, Natalia S; https://orcid.org/0000-0002-9294-9461, Datta, Indrani; https://orcid.org/0000-0001-7548-9881, Garofano, Luciano; https://orcid.org/0000-0001-8582-0865, Vallentgoed, Wies R; https://orcid.org/0000-0001-6373-7710, Varn, Frederick S; https://orcid.org/0000-0001-6307-016X, Aldape, Kenneth; https://orcid.org/0000-0001-5119-7550, D'Angelo, Fulvio; https://orcid.org/0000-0002-4940-4693, Bakas, Spyridon; https://orcid.org/0000-0001-8734-6482, Barnholtz-Sloan, Jill S; https://orcid.org/0000-0001-6190-9304, Gan, Hui K; https://orcid.org/0000-0001-7319-8546, Hasanain, Mohammad; https://orcid.org/0000-0001-5207-101X, Hau, Ann-Christin; https://orcid.org/0000-0002-4412-2355, Johnson, Kevin C; https://orcid.org/0000-0003-0016-5158, Cazacu, Simona; https://orcid.org/0000-0002-6085-4177, deCarvalho, Ana C; https://orcid.org/0000-0003-1183-4548, Khasraw, Mustafa; https://orcid.org/0000-0003-3249-9849, Kocakavuk, Emre; https://orcid.org/0000-0003-1920-0494, Kouwenhoven, Mathilde C M; https://orcid.org/0000-0001-5252-4365, Migliozzi, Simona; https://orcid.org/0000-0002-4870-8943, Niclou, Simone P; https://orcid.org/0000-0002-3417-9534, Niers, Johanna M; https://orcid.org/0000-0002-0366-8247, Ormond, D Ryan; https://orcid.org/0000-0001-7027-2915, Paek, Sun Ha; https://orcid.org/0000-0003-3007-8653, Reifenberger, Guido; https://orcid.org/0000-0002-1419-9837, Sillevis Smitt, Peter A; https://orcid.org/0000-0001-8044-6798, Smits, Marion; https://orcid.org/0000-0001-5563-2871, Weiss, Tobias; https://orcid.org/0000-0002-5533-9429, Weller, Michael; https://orcid.org/0000-0002-1748-174X, and et al

Abstract

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histological progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution towards an IDHwt-like phenotype.

Published
2024

13. The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen

Author

Malta, Tathiane M., Sabedot, Thais S., Morosini, Natalia S., Datta, Indrani, Garofano, Luciano, Vallentgoed, Wies, Varn, Frederick S., Aldape, Kenneth, D'Angelo, Fulvio, Bakas, Spyridon, Barnholtz-Sloan, Jill S., Gan, Hui K., Hasanain, Mohammad, Hau, Ann Christin, Johnson, Kevin C., Cazacu, Simona, deCarvalho, Ana C., Khasraw, Mustafa, Kocakavuk, Emre, Kouwenhoven, Mathilde C.M., Migliozzi, Simona, Niclou, Simone P., Niers, Johanna M., Ormond, D. Ryan, Paek, Sun Ha, Reifenberger, Guido, Smitt, Peter A.Sillevis, Smits, Marion, Stead, Lucy F., van den Bent, Martin J., Van Meir, Erwin G., Walenkamp, Annemiek, Weiss, Tobias, Weller, Michael, Westerman, Bart A., Ylstra, Bauke, Wesseling, Pieter, Lasorella, Anna, French, Pim J., Poisson, Laila M., Verhaak, Roel G.W., Iavarone, Antonio, Noushmehr, Houtan, Malta, Tathiane M., Sabedot, Thais S., Morosini, Natalia S., Datta, Indrani, Garofano, Luciano, Vallentgoed, Wies, Varn, Frederick S., Aldape, Kenneth, D'Angelo, Fulvio, Bakas, Spyridon, Barnholtz-Sloan, Jill S., Gan, Hui K., Hasanain, Mohammad, Hau, Ann Christin, Johnson, Kevin C., Cazacu, Simona, deCarvalho, Ana C., Khasraw, Mustafa, Kocakavuk, Emre, Kouwenhoven, Mathilde C.M., Migliozzi, Simona, Niclou, Simone P., Niers, Johanna M., Ormond, D. Ryan, Paek, Sun Ha, Reifenberger, Guido, Smitt, Peter A.Sillevis, Smits, Marion, Stead, Lucy F., van den Bent, Martin J., Van Meir, Erwin G., Walenkamp, Annemiek, Weiss, Tobias, Weller, Michael, Westerman, Bart A., Ylstra, Bauke, Wesseling, Pieter, Lasorella, Anna, French, Pim J., Poisson, Laila M., Verhaak, Roel G.W., Iavarone, Antonio, and Noushmehr, Houtan

Abstract

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype.

Published
2024

14. Pbx1 is required for adult subventricular zone neurogenesis.

Author

Grebbin, Britta Moyo, Hau, Ann-Christin, Groß, Anja, Anders-Maurer, Marie, Schramm, Jasmine, Koss, Matthew, Wille, Christoph, Mittelbronn, Michel, Selleri, Licia, and Schulte, Dorothea

Subjects
Lateral Ventricles, Olfactory Bulb, Oligodendroglia, Cells, Cultured, Stem Cells, Animals, Mice, Inbred C57BL, Tyrosine 3-Monooxygenase, Neuropeptides, Microtubule-Associated Proteins, Homeodomain Proteins, Proto-Oncogene Proteins, Transcription Factors, Gene Targeting, Cell Differentiation, Cell Movement, Cell Survival, Gene Expression Regulation, Developmental, Gene Deletion, Base Sequence, Protein Binding, Cell Lineage, Aging, Enhancer Elements, Genetic, Neurogenesis, Pre-B-Cell Leukemia Transcription Factor 1, Adult neurogenesis, Cell fate specification, Doublecortin, Pioneer factor, Subventricular zone, TALE-homeodomain protein, Biological Sciences, Medical and Health Sciences
Abstract

TALE-homeodomain proteins function as components of heteromeric complexes that contain one member each of the PBC and MEIS/PREP subclasses. We recently showed that MEIS2 cooperates with the neurogenic transcription factor PAX6 in the control of adult subventricular zone (SVZ) neurogenesis in rodents. Expression of the PBC protein PBX1 in the SVZ has been reported, but its functional role(s) has not been investigated. Using a genetic loss-of-function mouse model, we now show that Pbx1 is an early regulator of SVZ neurogenesis. Targeted deletion of Pbx1 by retroviral transduction of Cre recombinase into Pbx2-deficient SVZ stem and progenitor cells carrying floxed alleles of Pbx1 significantly reduced the production of neurons and increased the generation of oligodendrocytes. Loss of Pbx1 expression in neuronally committed neuroblasts in the rostral migratory stream in a Pbx2 null background, by contrast, severely compromised cell survival. By chromatin immunoprecipitation from endogenous tissues or isolated cells, we further detected PBX1 binding to known regulatory regions of the neuron-specific genes Dcx and Th days or even weeks before the respective genes are expressed during the normal program of SVZ neurogenesis, suggesting that PBX1 might act as a priming factor to mark these genes for subsequent activation. Collectively, our results establish that PBX1 regulates adult neural cell fate determination in a manner beyond that of its heterodimerization partner MEIS2.

Published
2016

15. The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen

Author

Malta, Tathiane M., primary, Sabedot, Thais S., additional, Morosini, Natalia S., additional, Datta, Indrani, additional, Garofano, Luciano, additional, Vallentgoed, Wies R., additional, Varn, Frederick S., additional, Aldape, Kenneth, additional, D'Angelo, Fulvio, additional, Bakas, Spyridon, additional, Barnholtz-Sloan, Jill S., additional, Gan, Hui K., additional, Hasanain, Mohammad, additional, Hau, Ann-Christin, additional, Johnson, Kevin C., additional, Cazacu, Simona, additional, deCarvalho, Ana C., additional, Khasraw, Mustafa, additional, Kocakavuk, Emre, additional, Kouwenhoven, Mathilde C.M., additional, Migliozzi, Simona, additional, Niclou, Simone P., additional, Niers, Johanna M., additional, Ormond, D. Ryan., additional, Paek, Sun Ha, additional, Reifenberger, Guido, additional, Sillevis Smitt, Peter A., additional, Smits, Marion, additional, Stead, Lucy F., additional, van den Bent, Martin J., additional, Van Meir, Erwin G., additional, Walenkamp, Annemiek, additional, Weiss, Tobias, additional, Weller, Michael, additional, Westerman, Bart A., additional, Ylstra, Bauke, additional, Wesseling, Pieter, additional, Lasorella, Anna, additional, French, Pim J., additional, Poisson, Laila M., additional, Consortium, The GLASS, additional, Verhaak, Roel G.W., additional, Iavarone, Antonio, additional, and Noushmehr, Houtan, additional

Published
2023
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16. Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

Author

Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anaïs, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sébastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, and Niclou, Simone P.

Published
2020
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18. The neuronal transcription factor MEIS2 is a calpain-2 protease target.

Author

Müller, Tanja, Reichlmeir, Marina, Hau, Ann-Christin, Wittig, Ilka, and Schulte, Dorothea

Subjects
TRANSCRIPTION factors, STEM cell niches, NEURAL stem cells, PROGENITOR cells, STEM cells
Abstract

Tight control over transcription factor activity is necessary for a sensible balance between cellular proliferation and differentiation in the embryo and during tissue homeostasis by adult stem cells, but mechanistic details have remained incomplete. The homeodomain transcription factor MEIS2 is an important regulator of neurogenesis in the ventricular-subventricular zone (V-SVZ) adult stem cell niche in mice. We here identify MEIS2 as direct target of the intracellular protease calpain-2 (composed of the catalytic subunit CAPN2 and the regulatory subunit CAPNS1). Phosphorylation at conserved serine and/or threonine residues, or dimerization with PBX1, reduced the sensitivity of MEIS2 towards cleavage by calpain-2. In the adult V-SVZ, calpain-2 activity is high in stem and progenitor cells, but rapidly declines during neuronal differentiation, which is accompanied by increased stability of MEIS2 full-length protein. In accordance with this, blocking calpain-2 activity in stem and progenitor cells, or overexpression of a cleavage-insensitive form of MEIS2, increased the production of neurons, whereas overexpression of a catalytically active CAPN2 reduced it. Collectively, our results support a key role for calpain-2 in controlling the output of adult V-SVZ neural stem and progenitor cells through cleavage of the neuronal fate determinant MEIS2. [ABSTRACT FROM AUTHOR]

Published
2024
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19. AN1-type zinc finger protein 3 (ZFAND3) is a transcriptional regulator that drives Glioblastoma invasion

Author

Schuster, Anne, Klein, Eliane, Neirinckx, Virginie, Knudsen, Arnon Møldrup, Fabian, Carina, Hau, Ann-Christin, Dieterle, Monika, Oudin, Anais, Nazarov, Petr V., Golebiewska, Anna, Muller, Arnaud, Perez-Hernandez, Daniel, Rodius, Sophie, Dittmar, Gunnar, Bjerkvig, Rolf, Herold-Mende, Christel, Klink, Barbara, Kristensen, Bjarne Winther, and Niclou, Simone P.

Published
2020
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20. Federated learning enables big data for rare cancer boundary detection

Author

Pati, Sarthak, primary, Baid, Ujjwal, additional, Edwards, Brandon, additional, Sheller, Micah, additional, Wang, Shih-Han, additional, Reina, G. Anthony, additional, Foley, Patrick, additional, Gruzdev, Alexey, additional, Karkada, Deepthi, additional, Davatzikos, Christos, additional, Sako, Chiharu, additional, Ghodasara, Satyam, additional, Bilello, Michel, additional, Mohan, Suyash, additional, Vollmuth, Philipp, additional, Brugnara, Gianluca, additional, Preetha, Chandrakanth J., additional, Sahm, Felix, additional, Maier-Hein, Klaus, additional, Zenk, Maximilian, additional, Bendszus, Martin, additional, Wick, Wolfgang, additional, Calabrese, Evan, additional, Rudie, Jeffrey, additional, Villanueva-Meyer, Javier, additional, Cha, Soonmee, additional, Ingalhalikar, Madhura, additional, Jadhav, Manali, additional, Pandey, Umang, additional, Saini, Jitender, additional, Garrett, John, additional, Larson, Matthew, additional, Jeraj, Robert, additional, Currie, Stuart, additional, Frood, Russell, additional, Fatania, Kavi, additional, Huang, Raymond Y., additional, Chang, Ken, additional, Balaña, Carmen, additional, Capellades, Jaume, additional, Puig, Josep, additional, Trenkler, Johannes, additional, Pichler, Josef, additional, Necker, Georg, additional, Haunschmidt, Andreas, additional, Meckel, Stephan, additional, Shukla, Gaurav, additional, Liem, Spencer, additional, Alexander, Gregory S., additional, Lombardo, Joseph, additional, Palmer, Joshua D., additional, Flanders, Adam E., additional, Dicker, Adam P., additional, Sair, Haris I., additional, Jones, Craig K., additional, Venkataraman, Archana, additional, Jiang, Meirui, additional, So, Tiffany Y., additional, Chen, Cheng, additional, Heng, Pheng Ann, additional, Dou, Qi, additional, Kozubek, Michal, additional, Lux, Filip, additional, Michálek, Jan, additional, Matula, Petr, additional, Keřkovský, Miloš, additional, Kopřivová, Tereza, additional, Dostál, Marek, additional, Vybíhal, Václav, additional, Vogelbaum, Michael A., additional, Mitchell, J. Ross, additional, Farinhas, Joaquim, additional, Maldjian, Joseph A., additional, Yogananda, Chandan Ganesh Bangalore, additional, Pinho, Marco C., additional, Reddy, Divya, additional, Holcomb, James, additional, Wagner, Benjamin C., additional, Ellingson, Benjamin M., additional, Cloughesy, Timothy F., additional, Raymond, Catalina, additional, Oughourlian, Talia, additional, Hagiwara, Akifumi, additional, Wang, Chencai, additional, To, Minh-Son, additional, Bhardwaj, Sargam, additional, Chong, Chee, additional, Agzarian, Marc, additional, Falcão, Alexandre Xavier, additional, Martins, Samuel B., additional, Teixeira, Bernardo C. A., additional, Sprenger, Flávia, additional, Menotti, David, additional, Lucio, Diego R., additional, LaMontagne, Pamela, additional, Marcus, Daniel, additional, Wiestler, Benedikt, additional, Kofler, Florian, additional, Ezhov, Ivan, additional, Metz, Marie, additional, Jain, Rajan, additional, Lee, Matthew, additional, Lui, Yvonne W., additional, McKinley, Richard, additional, Slotboom, Johannes, additional, Radojewski, Piotr, additional, Meier, Raphael, additional, Wiest, Roland, additional, Murcia, Derrick, additional, Fu, Eric, additional, Haas, Rourke, additional, Thompson, John, additional, Ormond, David Ryan, additional, Badve, Chaitra, additional, Sloan, Andrew E., additional, Vadmal, Vachan, additional, Waite, Kristin, additional, Colen, Rivka R., additional, Pei, Linmin, additional, Ak, Murat, additional, Srinivasan, Ashok, additional, Bapuraj, J. Rajiv, additional, Rao, Arvind, additional, Wang, Nicholas, additional, Yoshiaki, Ota, additional, Moritani, Toshio, additional, Turk, Sevcan, additional, Lee, Joonsang, additional, Prabhudesai, Snehal, additional, Morón, Fanny, additional, Mandel, Jacob, additional, Kamnitsas, Konstantinos, additional, Glocker, Ben, additional, Dixon, Luke V. M., additional, Williams, Matthew, additional, Zampakis, Peter, additional, Panagiotopoulos, Vasileios, additional, Tsiganos, Panagiotis, additional, Alexiou, Sotiris, additional, Haliassos, Ilias, additional, Zacharaki, Evangelia I., additional, Moustakas, Konstantinos, additional, Kalogeropoulou, Christina, additional, Kardamakis, Dimitrios M., additional, Choi, Yoon Seong, additional, Lee, Seung-Koo, additional, Chang, Jong Hee, additional, Ahn, Sung Soo, additional, Luo, Bing, additional, Poisson, Laila, additional, Wen, Ning, additional, Tiwari, Pallavi, additional, Verma, Ruchika, additional, Bareja, Rohan, additional, Yadav, Ipsa, additional, Chen, Jonathan, additional, Kumar, Neeraj, additional, Smits, Marion, additional, van der Voort, Sebastian R., additional, Alafandi, Ahmed, additional, Incekara, Fatih, additional, Wijnenga, Maarten M. J., additional, Kapsas, Georgios, additional, Gahrmann, Renske, additional, Schouten, Joost W., additional, Dubbink, Hendrikus J., additional, Vincent, Arnaud J. P. E., additional, van den Bent, Martin J., additional, French, Pim J., additional, Klein, Stefan, additional, Yuan, Yading, additional, Sharma, Sonam, additional, Tseng, Tzu-Chi, additional, Adabi, Saba, additional, Niclou, Simone P., additional, Keunen, Olivier, additional, Hau, Ann-Christin, additional, Vallières, Martin, additional, Fortin, David, additional, Lepage, Martin, additional, Landman, Bennett, additional, Ramadass, Karthik, additional, Xu, Kaiwen, additional, Chotai, Silky, additional, Chambless, Lola B., additional, Mistry, Akshitkumar, additional, Thompson, Reid C., additional, Gusev, Yuriy, additional, Bhuvaneshwar, Krithika, additional, Sayah, Anousheh, additional, Bencheqroun, Camelia, additional, Belouali, Anas, additional, Madhavan, Subha, additional, Booth, Thomas C., additional, Chelliah, Alysha, additional, Modat, Marc, additional, Shuaib, Haris, additional, Dragos, Carmen, additional, Abayazeed, Aly, additional, Kolodziej, Kenneth, additional, Hill, Michael, additional, Abbassy, Ahmed, additional, Gamal, Shady, additional, Mekhaimar, Mahmoud, additional, Qayati, Mohamed, additional, Reyes, Mauricio, additional, Park, Ji Eun, additional, Yun, Jihye, additional, Kim, Ho Sung, additional, Mahajan, Abhishek, additional, Muzi, Mark, additional, Benson, Sean, additional, Beets-Tan, Regina G. H., additional, Teuwen, Jonas, additional, Herrera-Trujillo, Alejandro, additional, Trujillo, Maria, additional, Escobar, William, additional, Abello, Ana, additional, Bernal, Jose, additional, Gómez, Jhon, additional, Choi, Joseph, additional, Baek, Stephen, additional, Kim, Yusung, additional, Ismael, Heba, additional, Allen, Bryan, additional, Buatti, John M., additional, Kotrotsou, Aikaterini, additional, Li, Hongwei, additional, Weiss, Tobias, additional, Weller, Michael, additional, Bink, Andrea, additional, Pouymayou, Bertrand, additional, Shaykh, Hassan F., additional, Saltz, Joel, additional, Prasanna, Prateek, additional, Shrestha, Sampurna, additional, Mani, Kartik M., additional, Payne, David, additional, Kurc, Tahsin, additional, Pelaez, Enrique, additional, Franco-Maldonado, Heydy, additional, Loayza, Francis, additional, Quevedo, Sebastian, additional, Guevara, Pamela, additional, Torche, Esteban, additional, Mendoza, Cristobal, additional, Vera, Franco, additional, Ríos, Elvis, additional, López, Eduardo, additional, Velastin, Sergio A., additional, Ogbole, Godwin, additional, Soneye, Mayowa, additional, Oyekunle, Dotun, additional, Odafe-Oyibotha, Olubunmi, additional, Osobu, Babatunde, additional, Shu’aibu, Mustapha, additional, Dorcas, Adeleye, additional, Dako, Farouk, additional, Simpson, Amber L., additional, Hamghalam, Mohammad, additional, Peoples, Jacob J., additional, Hu, Ricky, additional, Tran, Anh, additional, Cutler, Danielle, additional, Moraes, Fabio Y., additional, Boss, Michael A., additional, Gimpel, James, additional, Veettil, Deepak Kattil, additional, Schmidt, Kendall, additional, Bialecki, Brian, additional, Marella, Sailaja, additional, Price, Cynthia, additional, Cimino, Lisa, additional, Apgar, Charles, additional, Shah, Prashant, additional, Menze, Bjoern, additional, Barnholtz-Sloan, Jill S., additional, Martin, Jason, additional, and Bakas, Spyridon, additional

Published
2022
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24. EPCO-13. MULTIOMIC SINGLE NUCLEUS RNA- AND ATACseq PROFILING REVEALS REGULATORS OF GLIOMA CELL STATE DIVERSITY

Author

Anderson, Kevin, primary, Johnson, Kevin, additional, Varn, Frederick, additional, Bessonett, Shannon, additional, Gujar, Amit, additional, Flynn, Bill, additional, Courtois, Elise, additional, Hau, Ann-Christin, additional, Golebiewska, Anna, additional, Paek, Sun Ha, additional, Niclou, Simone, additional, Samuels, Michael, additional, Robson, Paul, additional, and Verhaak, Roel, additional

Published
2021
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25. Protocol for derivation of organoids and patient-derived orthotopic xenografts from glioma patient tumors

Author

Oudin, Anaïs, primary, Baus, Virginie, additional, Barthelemy, Vanessa, additional, Fabian, Carina, additional, Klein, Eliane, additional, Dieterle, Monika, additional, Wantz, May, additional, Hau, Ann-Christin, additional, Dording, Claire, additional, Bernard, Amandine, additional, Michelucci, Alessandro, additional, Yabo, Yahaya A., additional, Kanli, Georgia, additional, Keunen, Olivier, additional, Bjerkvig, Rolf, additional, Niclou, Simone P., additional, and Golebiewska, Anna, additional

Published
2021
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26. FSMP-07. CYSTATHIONINE-Γ-LYASE DRIVES ANTIOXIDANT DEFENSE IN CYSTEINE-RESTRICTED IDH1 MUTANT ASTROCYTOMAS

Author

Cano-Galiano, Andrés, primary, Oudin, Anais, additional, Fack, Fred, additional, Allega, Maria-Francesca, additional, Sumpton, David, additional, Martinez-Garcia, Elena, additional, Dittmar, Gunnar, additional, Hau, Ann-Christin, additional, Herold-Mende, Christel, additional, Bjerkvig, Rolf, additional, Meiser, Johannes, additional, Tardito, Saverio, additional, and Niclou, Simone P, additional

Published
2021
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27. Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology.

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Departmanet of Life Sciences and Medicine [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Neuropathology (Mittelbronn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Interventional Neuroscience (Hertel Group) [research center], n°7.4615.18/Télévie-FNRS [sponsor], n°7.4632.17/Télévie-FNRS [sponsor], 766069/H2020 Marie Skłodowska-Curie Actions [sponsor], Pan-RTK/Fondation Cancer Luxembourg [sponsor], PEARL award - P16/BM/11192868/Fonds National de la Recherche Luxembourg [sponsor], C17/BM/11664971 FNR [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anaïs, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sébastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, Niclou, Simone, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Departmanet of Life Sciences and Medicine [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Neuropathology (Mittelbronn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Interventional Neuroscience (Hertel Group) [research center], n°7.4615.18/Télévie-FNRS [sponsor], n°7.4632.17/Télévie-FNRS [sponsor], 766069/H2020 Marie Skłodowska-Curie Actions [sponsor], Pan-RTK/Fondation Cancer Luxembourg [sponsor], PEARL award - P16/BM/11192868/Fonds National de la Recherche Luxembourg [sponsor], C17/BM/11664971 FNR [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anaïs, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sébastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, and Niclou, Simone

Abstract

Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.

Published
2020

28. Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Author

Luxembourg Institute of Health - LIH [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Télévie-FNRS (Grants n°7.4632.17, 4615.18) [sponsor], Fondation Cancer Luxembourg (Pan-RTK Targeting) [sponsor], FNR; CORE Junior C17/BM/11664971/DEMICS [sponsor], GLIOTRAIN ITN funded by the European Union’s Horizon 2020 [sponsor], Marie Skłodowska-Curie grant agreement No 766069 [sponsor], FNR PEARL P16/BM/11192868 grant [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anais, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sebastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, Niclou, Simone, Luxembourg Institute of Health - LIH [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Télévie-FNRS (Grants n°7.4632.17, 4615.18) [sponsor], Fondation Cancer Luxembourg (Pan-RTK Targeting) [sponsor], FNR; CORE Junior C17/BM/11664971/DEMICS [sponsor], GLIOTRAIN ITN funded by the European Union’s Horizon 2020 [sponsor], Marie Skłodowska-Curie grant agreement No 766069 [sponsor], FNR PEARL P16/BM/11192868 grant [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anais, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sebastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, and Niclou, Simone

Abstract

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies.

Published
2020

29. Cystathionine-γ-lyase drives antioxidant defense in cysteine-restricted IDH1-mutant astrocytomas

Author

Cano-Galiano, Andrés, primary, Oudin, Anais, additional, Fack, Fred, additional, Allega, Maria-Francesca, additional, Sumpton, David, additional, Martinez-Garcia, Elena, additional, Dittmar, Gunnar, additional, Hau, Ann-Christin, additional, De Falco, Alfonso, additional, Herold-Mende, Christel, additional, Bjerkvig, Rolf, additional, Meiser, Johannes, additional, Tardito, Saverio, additional, and Niclou, Simone P, additional

Published
2021
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31. TMOD-08. PRIMARY AND RECURRENT GLIOMA PATIENT-DERIVED ORTHOTOPIC XENOGRAFTS (PDOX) REPRESENT RELEVANT PATIENT AVATARS FOR PRECISION MEDICINE

Author

Golebiewska, Anna, primary, Hau, Ann-Christin, additional, Oudin, Anais, additional, Stieber, Daniel, additional, Yabo, Yahaya A, additional, Kwon, Yong-Jun, additional, Klink, Barbara, additional, Skupin, Alexander, additional, Hertel, Frank, additional, Bjerkvig, Rolf, additional, and Niclou, Simone P, additional

Published
2020
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33. Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Author

Golebiewska, Anna, primary, Hau, Ann-Christin, additional, Oudin, Anaïs, additional, Stieber, Daniel, additional, Yabo, Yahaya A., additional, Baus, Virginie, additional, Barthelemy, Vanessa, additional, Klein, Eliane, additional, Bougnaud, Sébastien, additional, Keunen, Olivier, additional, Wantz, May, additional, Michelucci, Alessandro, additional, Neirinckx, Virginie, additional, Muller, Arnaud, additional, Kaoma, Tony, additional, Nazarov, Petr V., additional, Azuaje, Francisco, additional, De Falco, Alfonso, additional, Flies, Ben, additional, Richart, Lorraine, additional, Poovathingal, Suresh, additional, Arns, Thais, additional, Grzyb, Kamil, additional, Mock, Andreas, additional, Herold-Mende, Christel, additional, Steino, Anne, additional, Brown, Dennis, additional, May, Patrick, additional, Miletic, Hrvoje, additional, Malta, Tathiane M., additional, Noushmehr, Houtan, additional, Kwon, Yong-Jun, additional, Jahn, Winnie, additional, Klink, Barbara, additional, Tanner, Georgette, additional, Stead, Lucy F., additional, Mittelbronn, Michel, additional, Skupin, Alexander, additional, Hertel, Frank, additional, Bjerkvig, Rolf, additional, and Niclou, Simone P., additional

Published
2020
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35. GENE-02. ESTABLISHING PERSONALIZED TREATMENT OPTIONS FOR RECURRENT HIGH-GRADE GLIOMAS

Author

Hau, Ann-Christin, primary, Houben, Linsey, additional, Klein, Eliane, additional, Oudin, Anais, additional, Stieber, Daniel, additional, Flies, Ben, additional, Kaoma, Tony, additional, Azuaje, Fransisco, additional, Fritah, Sabrina, additional, Bjerkvig, Rolf, additional, Mittelbronn, Michel, additional, Hertel, Frank, additional, Golebiewska, Anna, additional, and Niclou, Simone, additional

Published
2019
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36. The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma

Author

Neirinckx, Virginie, primary, Hau, Ann-Christin, primary, Schuster, Anne, primary, Fritah, Sabrina, primary, Tiemann, Katja, primary, Klein, Eliane, primary, Nazarov, Petr V, primary, Matagne, André, primary, Szpakowska, Martyna, primary, Meyrath, Max, primary, Chevigné, Andy, primary, Schmidt, Mirko H H, primary, and Niclou, Simone P, primary

Published
2019
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38. TMOD-29. MOLECULAR CHARACTERIZATION OF GLIOMA PATIENT-DERIVED ORTHOTOPIC XENOGRAFTS: FROM BASIC RESEARCH TO PRECLINICAL STUDIES

Author

Hau, Ann-Christin, primary, Golebiewska, Anna, additional, Oudin, Anais, additional, Houben, Linsey, additional, Stieber, Daniel, additional, Azuaje, Francisco, additional, Kaoma, Tony, additional, Muller, Arnaud, additional, Hertel, Frank, additional, Mittelbronn, Michel, additional, Bjerkvig, Rolf, additional, and Niclou, Simone, additional

Published
2018
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39. Arginine methylation regulates MEIS2 nuclear localization to promote neuronal differentiation of adult SVZ progenitors

Author

Kolb, Jasmine, Anders-Maurer, Marie, Müller, Tanja, Hau, Ann-Christin, Grebbin, Britta Moyo, Kallenborn-Gerhardt, Wiebke, Behrends, Christian, Schulte, Dorothea, Kolb, Jasmine, Anders-Maurer, Marie, Müller, Tanja, Hau, Ann-Christin, Grebbin, Britta Moyo, Kallenborn-Gerhardt, Wiebke, Behrends, Christian, and Schulte, Dorothea

Abstract

Adult neurogenesis is regulated by stem cell niche-derived extrinsic factors and cell-intrinsic regulators, yet the mechanisms by which niche signals impinge on the activity of intrinsic neurogenic transcription factors remain poorly defined. Here, we report that MEIS2, an essential regulator of adult SVZ neurogenesis, is subject to posttranslational regulation in the SVZ olfactory bulb neurogenic system. Nuclear accumulation of MEIS2 in adult SVZ-derived progenitor cells follows downregulation of EGFR signaling and is modulated by methylation of MEIS2 on a conserved arginine, which lies in close proximity to nested binding sites for the nuclear export receptor CRM1 and the MEIS dimerization partner PBX1. Methylation impairs interaction with CRM1 without affecting PBX1 dimerization and thereby allows MEIS2 nuclear accumulation, a prerequisite for neuronal differentiation. Our results describe a form of posttranscriptional modulation of adult SVZ neurogenesis whereby an extrinsic signal fine-tunes neurogenesis through posttranslational modification of a transcriptional regulator of cell fate.

Published
2018

40. Glioma Through the Looking GLASS: the Glioma Longitudinal Analysis consortium, molecular evolution of diffuse gliomas

Author

Aldape, Kenneth, Amin, Samirkumar B, Ashley, David M, Barnholtz-Sloan, Jill S, Bates, Amanda J, Beroukhim, Rameen, Bock, Christoph, Brat, Daniel J, Claus, Elizabeth B, Costello, Joseph F, de Groot, John F, Finocchiaro, Gaetano, French, Pim J, Gan, Hui K, Griffith, Brent, Herold-Mende, Christel C, Horbinski, Craig, Iavarone, Antonio, Kalkanis, Steven N, Karabatsou, Konstantina, Kim, Hoon, Kouwenhoven, Mathilde CM, McDonald, Kerrie L, Miletic, Hrvoje, Nam, Do-Hyun, Ng, Ho Keung, Niclou, Simone P, Noushmehr, Houtan, Ormond, D Ryan, Poisson, Laila M, Reifenberger, Guido, Roncaroli, Federico, Sa, Jason K, Sillevis Smitt, Peter AE, Smits, Marion, Souza, Camila F, Tabatabai, Ghazaleh, Van Meir, Erwin G, Verhaak, Roel GW, Watts, Colin, Wesseling, Pieter, Woehrer, Adelheid, Yung, WK Alfred, Jungk, Christine, Hau, Ann-Christin, Dyck, Eric van, Westerman, Bart A, Yin, Julia, Abiola, Olajide, Khasraw, Mustafa, Sulman, Erik P, and Muscat, Andrea M

Subjects
Oncology, 0303 health sciences, medicine.medical_specialty, Disease, Biology, medicine.disease, Bioinformatics, Phenotype, 3. Good health, Malignant transformation, 03 medical and health sciences, Diffuse Glioma, 0302 clinical medicine, Molecular evolution, 030220 oncology & carcinogenesis, Glioma, Internal medicine, Cancer genome, medicine, 030304 developmental biology, Epigenomics
Abstract

Adult diffuse glioma are a diverse group of intracranial neoplasms associated with a disproportional large number of productive life years lost, thus imposing a highly emotional and significant financial burden on society. Patient death is the result of an aggressive course of disease following diagnosis. The Cancer Genome Atlas and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant molecular evolution during the malignant transformation. We review current knowledge on genomic, epigenomic and transcriptomic abnormalities before and after disease recurrence. We outline an effort to systemically catalogue the longitudinal changes in gliomas, the Glioma Longitudinal Analysis Consortium. The GLASS initiative will provide essential insights into the evolution of glioma towards a lethal phenotype with the potential to reveal targetable vulnerabilities, and ultimately, improved outcomes for a patient population in need.

Published
2017
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43. Pbx1 is required for adult SVZ neurogenesis

Author

Grebbin, Britta Moyo, primary, Hau, Ann-Christin, additional, Groß, Anja, additional, Anders-Maurer, Marie, additional, Schramm, Jasmine, additional, Koss, Matthew, additional, Wille, Christoph, additional, Mittelbronn, Michel, additional, Selleri, Licia, additional, and Schulte, Dorothea, additional

Published
2016
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45. The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen.

Author

Malta TM, Sabedot TS, Morosini NS, Datta I, Garofano L, Vallentgoed W, Varn FS, Aldape K, D'Angelo F, Bakas S, Barnholtz-Sloan JS, Gan HK, Hasanain M, Hau AC, Johnson KC, Cazacu S, deCarvalho AC, Khasraw M, Kocakavuk E, Kouwenhoven MCM, Migliozzi S, Niclou SP, Niers JM, Ormond DR, Paek SH, Reifenberger G, Sillevis Smitt PA, Smits M, Stead LF, van den Bent MJ, Van Meir EG, Walenkamp A, Weiss T, Weller M, Westerman BA, Ylstra B, Wesseling P, Lasorella A, French PJ, Poisson LM, Verhaak RGW, Iavarone A, and Noushmehr H

Subjects
Humans, Epigenesis, Genetic, Epigenomics, Mutation, Neoplasm Recurrence, Local genetics, Tumor Microenvironment, Brain Neoplasms pathology, Glioma pathology, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism
Abstract

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype., Significance: Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma., (©2023 The Authors; Published by the American Association for Cancer Research.)

Published
2024
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