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1. IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy

Author

Tanner, Georgette, Barrow, Rhiannon, Ajaib, Shoaib, Al-Jabri, Muna, Ahmed, Nazia, Pollock, Steven, Finetti, Martina, Rippaus, Nora, Bruns, Alexander F., Syed, Khaja, Poulter, James A., Matthews, Laura, Hughes, Thomas, Wilson, Erica, Johnson, Colin, Varn, Frederick S., Brüning-Richardson, Anke, Hogg, Catherine, Droop, Alastair, Gusnanto, Arief, Care, Matthew A., Cutillo, Luisa, Westhead, David R., Short, Susan C., Jenkinson, Michael D., Brodbelt, Andrew, Chakrabarty, Aruna, Ismail, Azzam, Verhaak, Roel G. W., and Stead, Lucy F.

Published
2024
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2. Glioma progression is shaped by genetic evolution and microenvironment interactions

Author

Varn, Frederick S, Johnson, Kevin C, Martinek, Jan, Huse, Jason T, Nasrallah, MacLean P, Wesseling, Pieter, Cooper, Lee AD, Malta, Tathiane M, Wade, Taylor E, Sabedot, Thais S, Brat, Daniel, Gould, Peter V, Wöehrer, Adelheid, Aldape, Kenneth, Ismail, Azzam, Sivajothi, Santhosh K, Barthel, Floris P, Kim, Hoon, Kocakavuk, Emre, Ahmed, Nazia, White, Kieron, Datta, Indrani, Moon, Hyo-Eun, Pollock, Steven, Goldfarb, Christine, Lee, Ga-Hyun, Garofano, Luciano, Anderson, Kevin J, Nehar-Belaid, Djamel, Barnholtz-Sloan, Jill S, Bakas, Spyridon, Byrne, Annette T, D’Angelo, Fulvio, Gan, Hui K, Khasraw, Mustafa, Migliozzi, Simona, Ormond, D Ryan, Paek, Sun Ha, Van Meir, Erwin G, Walenkamp, Annemiek ME, Watts, Colin, Weiss, Tobias, Weller, Michael, Palucka, Karolina, Stead, Lucy F, Poisson, Laila M, Noushmehr, Houtan, Iavarone, Antonio, Verhaak, Roel GW, Consortium, The GLASS, Alfaro, Kristin D, Amin, Samirkumar B, Ashley, David M, Bock, Christoph, Brodbelt, Andrew, Bulsara, Ketan R, and Castro, Ana Valeria

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Brain Disorders, Brain Cancer, Genetics, Cancer, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Adult, Brain Neoplasms, Evolution, Molecular, Genes, p16, Glioma, Humans, Isocitrate Dehydrogenase, Mutation, Neoplasm Recurrence, Local, Tumor Microenvironment, GLASS Consortium, genomics, glioblastoma, glioma, hypermutation, macrophages, microenvironment, neurons, single-cell, spatial imaging, treatment resistance, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Published
2022

3. Longitudinal molecular trajectories of diffuse glioma in adults

Author

Barthel, Floris P, Johnson, Kevin C, Varn, Frederick S, Moskalik, Anzhela D, Tanner, Georgette, Kocakavuk, Emre, Anderson, Kevin J, Abiola, Olajide, Aldape, Kenneth, Alfaro, Kristin D, Alpar, Donat, Amin, Samirkumar B, Ashley, David M, Bandopadhayay, Pratiti, Barnholtz-Sloan, Jill S, Beroukhim, Rameen, Bock, Christoph, Brastianos, Priscilla K, Brat, Daniel J, Brodbelt, Andrew R, Bruns, Alexander F, Bulsara, Ketan R, Chakrabarty, Aruna, Chakravarti, Arnab, Chuang, Jeffrey H, Claus, Elizabeth B, Cochran, Elizabeth J, Connelly, Jennifer, Costello, Joseph F, Finocchiaro, Gaetano, Fletcher, Michael N, French, Pim J, Gan, Hui K, Gilbert, Mark R, Gould, Peter V, Grimmer, Matthew R, Iavarone, Antonio, Ismail, Azzam, Jenkinson, Michael D, Khasraw, Mustafa, Kim, Hoon, Kouwenhoven, Mathilde CM, LaViolette, Peter S, Li, Meihong, Lichter, Peter, Ligon, Keith L, Lowman, Allison K, Malta, Tathiane M, Mazor, Tali, McDonald, Kerrie L, Molinaro, Annette M, Nam, Do-Hyun, Nayyar, Naema, Ng, Ho Keung, Ngan, Chew Yee, Niclou, Simone P, Niers, Johanna M, Noushmehr, Houtan, Noorbakhsh, Javad, Ormond, D Ryan, Park, Chul-Kee, Poisson, Laila M, Rabadan, Raul, Radlwimmer, Bernhard, Rao, Ganesh, Reifenberger, Guido, Sa, Jason K, Schuster, Michael, Shaw, Brian L, Short, Susan C, Smitt, Peter A Sillevis, Sloan, Andrew E, Smits, Marion, Suzuki, Hiromichi, Tabatabai, Ghazaleh, Van Meir, Erwin G, Watts, Colin, Weller, Michael, Wesseling, Pieter, Westerman, Bart A, Widhalm, Georg, Woehrer, Adelheid, Yung, WK Alfred, Zadeh, Gelareh, Huse, Jason T, De Groot, John F, Stead, Lucy F, and Verhaak, Roel GW

Subjects
Neurosciences, Brain Disorders, Cancer, Rare Diseases, Brain Cancer, Genetics, Adult, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 19, Disease Progression, Glioma, Humans, Isocitrate Dehydrogenase, Mutation, Polymorphism, Single Nucleotide, Recurrence, GLASS Consortium, General Science & Technology
Abstract

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

Published
2019

5. 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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6. 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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7. 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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8. 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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9. 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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10. Adult brain tumour research in 2024: Status, challenges and recommendations

Author

Purshouse, Karin, primary, Bulbeck, Helen J., additional, Rooney, Alasdair G., additional, Noble, Karen E., additional, Carruthers, Ross D., additional, Thompson, Gerard, additional, Hamerlik, Petra, additional, Yap, Christina, additional, Kurian, Kathreena M., additional, Jefferies, Sarah J., additional, Lopez, Juanita S., additional, Jenkinson, Michael D., additional, Hanemann, C. Oliver, additional, and Stead, Lucy F., additional

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., 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

13. 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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14. 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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17. EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma

Author

Struve, Nina, Binder, Zev A., Stead, Lucy F., Brend, Tim, Bagley, Stephen J., Faulkner, Claire, Ott, Leonie, Müller-Goebel, Justus, Weik, Anna-Sophie, Hoffer, Konstantin, Krug, Leonie, Rieckmann, Thorsten, Bußmann, Lara, Henze, Marvin, Morrissette, Jennifer J. D., Kurian, Kathreena M., Schüller, Ulrich, Petersen, Cordula, Rothkamm, Kai, O´ Rourke, Donald M., Short, Susan C., and Kriegs, Malte

Published
2020
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21. Experimental workflow from A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Author

Humphries, Matthew P., primary, Sundara Rajan, Sreekumar, primary, Droop, Alastair, primary, Suleman, Charlotte A.B., primary, Carbone, Carmine, primary, Nilsson, Cecilia, primary, Honarpisheh, Hedieh, primary, Cserni, Gabor, primary, Dent, Jo, primary, Fulford, Laura, primary, Jordan, Lee B., primary, Jones, J. Louise, primary, Kanthan, Rani, primary, Litwiniuk, Maria, primary, Di Benedetto, Anna, primary, Mottolese, Marcella, primary, Provenzano, Elena, primary, Shousha, Sami, primary, Stephens, Mark, primary, Walker, Rosemary A., primary, Kulka, Janina, primary, Ellis, Ian O., primary, Jeffery, Margaret, primary, Thygesen, Helene H., primary, Cappelletti, Vera, primary, Daidone, Maria G., primary, Hedenfalk, Ingrid A., primary, Fjällskog, Marie-Louise, primary, Melisi, Davide, primary, Stead, Lucy F., primary, Shaaban, Abeer M., primary, and Speirs, Valerie, primary

Published
2023
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22. Cut-off determination and representative staining profiles for eIF proteins determined by immunohistochemistry from A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Author

Humphries, Matthew P., primary, Sundara Rajan, Sreekumar, primary, Droop, Alastair, primary, Suleman, Charlotte A.B., primary, Carbone, Carmine, primary, Nilsson, Cecilia, primary, Honarpisheh, Hedieh, primary, Cserni, Gabor, primary, Dent, Jo, primary, Fulford, Laura, primary, Jordan, Lee B., primary, Jones, J. Louise, primary, Kanthan, Rani, primary, Litwiniuk, Maria, primary, Di Benedetto, Anna, primary, Mottolese, Marcella, primary, Provenzano, Elena, primary, Shousha, Sami, primary, Stephens, Mark, primary, Walker, Rosemary A., primary, Kulka, Janina, primary, Ellis, Ian O., primary, Jeffery, Margaret, primary, Thygesen, Helene H., primary, Cappelletti, Vera, primary, Daidone, Maria G., primary, Hedenfalk, Ingrid A., primary, Fjällskog, Marie-Louise, primary, Melisi, Davide, primary, Stead, Lucy F., primary, Shaaban, Abeer M., primary, and Speirs, Valerie, primary

Published
2023
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23. Interrogation of Oncomine{trade mark, serif} from A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Author

Humphries, Matthew P., primary, Sundara Rajan, Sreekumar, primary, Droop, Alastair, primary, Suleman, Charlotte A.B., primary, Carbone, Carmine, primary, Nilsson, Cecilia, primary, Honarpisheh, Hedieh, primary, Cserni, Gabor, primary, Dent, Jo, primary, Fulford, Laura, primary, Jordan, Lee B., primary, Jones, J. Louise, primary, Kanthan, Rani, primary, Litwiniuk, Maria, primary, Di Benedetto, Anna, primary, Mottolese, Marcella, primary, Provenzano, Elena, primary, Shousha, Sami, primary, Stephens, Mark, primary, Walker, Rosemary A., primary, Kulka, Janina, primary, Ellis, Ian O., primary, Jeffery, Margaret, primary, Thygesen, Helene H., primary, Cappelletti, Vera, primary, Daidone, Maria G., primary, Hedenfalk, Ingrid A., primary, Fjällskog, Marie-Louise, primary, Melisi, Davide, primary, Stead, Lucy F., primary, Shaaban, Abeer M., primary, and Speirs, Valerie, primary

Published
2023
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24. IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy

Author

Tanner, Georgette, primary, Barrow, Rhiannon, additional, Finetti, Martina, additional, Ajaib, Shoaib, additional, Ahmed, Nazia, additional, Pollock, Steven, additional, Rippaus, Nora, additional, Bruns, Alexander F., additional, Syed, Khaja, additional, Poulter, James, additional, Wilson, Erica, additional, Johnson, Colin, additional, Varn, Frederick S., additional, Brüning-Richardson, Anke, additional, Hogg, Catherine, additional, Droop, Alastair, additional, Gusnanto, Arief, additional, Care, Matthew A., additional, Cutillo, Luisa, additional, Westhead, David, additional, Short, Susan C., additional, Jenkinson, Michael D., additional, Brodbelt, Andrew, additional, Chakrabarty, Aruna, additional, Ismail, Azzam, additional, Verhaak, Roel GW, additional, and Stead, Lucy F., additional

Published
2023
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26. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade

Author

Samson, Adel, Scott, Karen J., Taggart, David, West, Emma J., Wilson, Erica, Nuovo, Gerard J., Thomson, Simon, Corns, Robert, Mathew, Ryan K., Fuller, Martin J., Kottke, Timothy J., Thompson, Jill M., Ilett, Elizabeth J., Cockle, Julia V., van Hille, Philip, Sivakumar, Gnanamurthy, Polson, Euan S., Turnbull, Samantha J., Appleton, Elizabeth S., Migneco, Gemma, Rose, Ailsa S., Coffey, Matthew C., Beirne, Deborah A., Collinson, Fiona J., Ralph, Christy, Alan Anthoney, D., Twelves, Christopher J., Furness, Andrew J., Quezada, Sergio A., Wurdak, Heiko, Errington-Mais, Fiona, Pandha, Hardev, Harrington, Kevin J., Selby, Peter J., Vile, Richard G., Griffin, Stephen D., Stead, Lucy F., Short, Susan C., and Melcher, Alan A.

Published
2018
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27. GBMdeconvoluteR accurately infers proportions of neoplastic and immune cell populations from bulk glioblastoma transcriptomics data

Author

Ajaib, Shoaib, primary, Lodha, Disha, additional, Pollock, Steven, additional, Hemmings, Gemma, additional, Finetti, Martina A, additional, Gusnanto, Arief, additional, Chakrabarty, Aruna, additional, Ismail, Azzam, additional, Wilson, Erica, additional, Varn, Frederick S, additional, Hunter, Bethany, additional, Filby, Andrew, additional, Brockman, Asa A, additional, McDonald, David, additional, Verhaak, Roel G W, additional, Ihrie, Rebecca A, additional, and Stead, Lucy F, additional

Published
2023
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28. Investigating the effects of arginine methylation inhibitors on microdissected brain tumour biopsies maintained in a miniaturised perfusion system

Author

Barry, Antonia, primary, Samuel, Sabrina F., additional, Hosni, Ines, additional, Moursi, Amr, additional, Feugere, Lauric, additional, Sennett, Christopher J., additional, Deepak, Srihari, additional, Achawal, Shailendra, additional, Rajaraman, Chittoor, additional, Iles, Alexander, additional, Wollenberg Valero, Katharina C., additional, Scott, Ian S., additional, Green, Vicky, additional, Stead, Lucy F., additional, Greenman, John, additional, Wade, Mark A., additional, and Beltran-Alvarez, Pedro, additional

Published
2023
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29. GBMdeconvoluteR accurately infers proportions of neoplastic and immune cell populations from bulk glioblastoma transcriptomics data

Author

Ajaib, Shoaib, primary, Lodha, Disha, additional, Pollock, Steven, additional, Hemmings, Gemma, additional, Finetti, Martina A., additional, Gusnanto, Arief, additional, Chakrabarty, Aruna, additional, Ismail, Azzam, additional, Wilson, Erica, additional, Varn, Frederick S, additional, Hunter, Bethany, additional, Filby, Andrew, additional, Brockman, Asa A., additional, McDonald, David, additional, Verhaak, Roel GW, additional, Ihrie, Rebecca A., additional, and Stead, Lucy F., additional

Published
2022
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30. The Challenges Faced in the Education of Biomedical Science Curriculum

Author

Estrada, Tânia, Cipriano, Maria A., Silva, Maria F., Abrantes, Ana M., Botelho, Maria F., Martins, Diana, Teixeira, Paulo, Mendes, Fernando, Andrew, Joanna, Berndt, Anne L., Al Amri, Waleed S., Allinson, Lisa M., Baxter, Diana E., Bell, Sandra M., Hanby, Andrew M., Jones, Stacey J., Shaaban, Abeer M., Stead, Lucy F., Verghese, Eldo T., Hughes, Thomas A., Dahham, Saad S., Al-Foudhili, Noor, Ahmed, Ikhlas, Al-Kharusi, Safiya, Al-Bahlani, Shadia, Burney, Ikram, Al-Dhahli, Buthaina, Al-Kharousi, Fakhra, Al-Kalbani, Amani, Mandhari, Mansour Al, Falahi, Karima Al, Pathare, Anil, Cunningham, Margerate, Al-Arimi, Zainab, Al-Muhaidhri, Raya, Al-Lawati, Hawraa, Al-Khan, Shathya, Al-Subhi, Maisoon, Ahmed, Samya, Al-Habsi, Khalid, Al-Bulushi, Fatma, Al-Sheryani, Jalila, Al-Marhoobi, Ali, Al-Hosni, Saif, Al-Omairi, Ishaq, Al-Mahroqi, Sabah, Boulassel, Mohmaed-Rachid, Al-Kindi, Fatima, Al-Saqri, Atika, Tamimi, Yahya, Al-Moundhri, Mansour, Ben Khalid, Dhoha, Sami, Hiba, Jabri, Zaima Al, Al-Quraini, Munawer, Khan, Fatima, Singh, Anuradha, Zafar, Nusrat, Adawi, Badriya Al, Rizvi, Meher, Al-Wahaibi, Loai, Al-Sudairi, Rajaa, Balkhair, Abdullah, Al-Owaisi, Huda, Mabruk, Mohamed, Al-Jabri, Zaaima, Al-Hinai, Amal, Al-Bimani, Atika, Al-Shabibi, Ammar, Al-Shabibi, Zahra, Al-Balushi, Badriya, Al-Badi, Hajer M., Al-Masrouri, Noha M., Al-Wahaibi, Nasar Y., Al-Sinawi, Shadia S., Al-Dairi, Najat, Al-Dighaishi, Malika, Shalaby, Asem, Morra, Mohamed, Adham, Sirin A., Al-Zeheimi, Noura, Eweas, Ahmad F., Abdallah, Qasem M.A., Norstedt, Gunnar, Al-Kharusi, A., Gräslund, T., Yu, S., Zadjali, Fahad, Kumar, Prashant, Yao, Ying, Bissler, John, Siddiqi, Najam, Nizwani, Nasser A., Al-Ghafri, Fatima, Al-Kindi, Mohammad, Al-Nabhani, Abdul Rahman, Shaikh, Zoya, Bait-Suwailam, Mohammed M., Al-Busaidi, Omar, Al-Shahimi, Ahmed, Al-Shizawi, Mohammed, Al-Qanuni, Muhanna, Matar, Abdulrahman, Al-Balushi, Moosa, Al-Rawahi, Samira, Al-Maskari, Muna, Al-Habsi, Sara, Al-Zadjali, Amani, Egan, Karl, Áinl, Fionnuala Ní, Al Fana, Zainab A., Al-Muhaidri, Raya, Al-Lawati, Hawra, Al-Belushi, Mazin, Al-Mashaykhi, Louza, Lawati, Hawra Al, Alarimi, Zainab Al fana, Al-Kindi, Mariya H. N., Al-Maawali, Mayyadah, Malgundkar, Shika, Al-Kalbani, Moza, Okamoto, Aikou, Waly, Mostafa I., Al-Balushi, Ruqaiya M., Prabakar, Preeja, Al-Shekaili, Atikah M.S., Ali, Amanat, Al-Mamari, Issa S., Al-Adawi, Badriya, Alam, Tanveer, Najam, Lubna, Khan, Ajmal, Khan, Sobia A., Al-Harrasi, Ahmed, Al-Lawati, Zainab, Khamis, Faryal A., Al-Hamdani, Aisha, Ramadhan, Fatma A., Al Rawahi, Thuria R., Al-Kobaisi, Muhannad F., Al-Dighaishi, Sirin, Al-Hadidi, Zuweina R., Al-Bulushi, Khadija H., Al-Alawi, Zaina M., Al-Abri, Nadia Y., Al-Rawahi, Shaikha S., Al-Bahlani, Shadia M., Al-Sibani, Asma, Al-Kharusi, Amira, Al-Balushi, Najwa, Al-Musalhi, Abdullah, Parsaei, Pouya, Asadi, Sayyed Y., Ezzati, Sareh, Karimi, Mehrdad, Rafieian-Kopaei, Mahmoud, Esfahani, Reyhaneh N., Alawi, Reem Al, Hamdani, Mohamed Al, Hoheisel, Jorg D., Baqi, Younis, Subhi, Ebtihal Al, Salmani, Majid Al, Al Maamari, Aasem T., Balakrishanan, E., Sundararajan, Narasimman, Al-Hassani, Khadija A., Nasir, Haniffa M., Sundararajan, N., Kumar, Anil, Santos, Rosaysela, and Klinkhachorn, Penprapa S.

Subjects
Conference Abstracts
Published
2021

33. 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

34. 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

38. 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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41. RBTT-06. TESSA JOWELL BRAIN MATRIX STUDY: A BRITISH FEASIBILITY STUDY OF MOLECULAR STRATIFICATION AND TARGETED THERAPY TO OPTIMIZE THE CLINICAL MANAGEMENT OF PATIENTS WITH GLIOMA

Author

Watts, Colin, primary, Apps, John, additional, Ansorg, Olaf, additional, Savage, Josh, additional, Fox, Richard, additional, Chalmers, Anthony, additional, Short, Susan C, additional, Thompson, Gerard, additional, Waldman, Adam, additional, Capper, David, additional, Hargrave, Darren, additional, Brennan, Paul, additional, Smith, Stuart, additional, Ashkan, Keyoumars, additional, Wykes, Victoria, additional, Kurian, Kathreena, additional, Jamal-Hanjani, Mariam, additional, Swanton, Charles, additional, Buckle, Peter, additional, Bulbeck, Helen, additional, Stead, Lucy F, additional, Vivanco, Igor, additional, and Bowden, Sarah, additional

Published
2019
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42. CBMT-16. EGFRvIII EXPRESSION CONFERS CHEMOSENSITIVITY BY INCREASING DNA MISMATCH REPAIR PROTEIN EXPRESSION AND REPLICATION STRESS

Author

Struve, Nina, primary, Binder, Zev A, additional, Stead, Lucy F, additional, Brend, Tim, additional, Bagley, Stephen J, additional, Faulkner, Claire, additional, Ott, Leonie, additional, Müller-Goebel, Justus, additional, Weik, Anna-Sophie, additional, Hoffer, Konstantin, additional, Rieckmann, Thorsten, additional, Christin Parplys, Ann, additional, Burmester, Jasmin, additional, Henze, Marvin, additional, Morrissette, Jennifer J D, additional, Schüller, Ulrich, additional, Petersen, Cordula, additional, Rothkamm, Kai, additional, Kurian, Kathreena M, additional, Short, Susan C, additional, and Kriegs, Malte, additional

Published
2019
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43. Upregulated WEE1 protects endothelial cells of colorectal cancer liver metastases

Author

Webster, Peter J., Littlejohns, Anna T., Gaunt, Hannah J., Young, Richard S., Rode, Baptiste, Ritchie, Judith E., Stead, Lucy F., Harrison, Sally, Droop, Alastair, Martin, Heather L., Tomlinson, Darren C., Hyman, Adam J., Appleby, Hollie L., Boxall, Sally, Bruns, Alexander F., Li, Jing, Prasad, Raj K., Lodge, J. Peter A., Burke, Dermot A., and Beech, David J.

Subjects
Neovascularization, Pathologic, Caspase 3, Liver Neoplasms, Endothelial Cells, Nuclear Proteins, colorectal cancer, Apoptosis, Cell Cycle Proteins, Protein-Tyrosine Kinases, Platelet Endothelial Cell Adhesion Molecule-1, angiogenesis, checkpoint kinase, endothelial cell, DNA damage, Humans, DNA Breaks, Double-Stranded, Colorectal Neoplasms, Research Paper
Abstract

Surgical resection of colorectal cancer liver metastases (CLM) can be curative, yet 80% of patients are unsuitable for this treatment. As angiogenesis is a determinant of CLM progression we isolated endothelial cells from CLM and sought a mechanism which is upregulated, essential for angiogenic properties of these cells and relevant to emerging therapeutic options. Matched CLM endothelial cells (CLMECs) and endothelial cells of normal adjacent liver (LiECs) were superficially similar but transcriptome sequencing revealed molecular differences, one of which was unexpected upregulation and functional significance of the checkpoint kinase WEE1. Western blotting confirmed that WEE1 protein was upregulated in CLMECs. Knockdown of WEE1 by targeted short interfering RNA or the WEE1 inhibitor AZD1775 suppressed proliferation and migration of CLMECs. Investigation of the underlying mechanism suggested induction of double-stranded DNA breaks due to nucleotide shortage which then led to caspase 3-dependent apoptosis. The implication for CLMEC tube formation was striking with AZD1775 inhibiting tube branch points by 83%. WEE1 inhibitors might therefore be a therapeutic option for CLM and could be considered more broadly as anti-angiogenic agents in cancer treatment.

Published
2017

45. Chemically-induced Neurite-like Outgrowth Reveals Multicellular Network Function in Patient-derived Glioblastoma Cells

Author

da Silva, Barbara, Irving, Bronwyn K., Polson, Euan S., Droop, Alastair, Griffiths, Hollie B.S., Mathew, Ryan K., Stead, Lucy F., Marrison, Joanne, Williams, Courtney, Williams, Jennifer, Short, Susan C., Scarcia, Margherita, O'Toole, Peter John, Allison, Simon J., Mavria, Georgia, and Wurdak, Heiko

Abstract

Tumor stem cells and malignant multicellular networks have been separately implicated in the therapeutic resistance of Glioblastoma Multiforme (GBM), the most aggressive type of brain cancer in adults. We show that small molecule inhibition of RHO-associated serine/threonine kinase (ROCKi) significantly promoted the outgrowth of neurite-like cell projections in cultures of heterogeneous patient-derived GBM stem-like cells. These projections formed de novo -induced cellular network (iNet) ‘webs’, which regressed after withdrawal of ROCKi. Connected cells within the iNet web exhibited long range calcium signal transmission, and significant lysosomal and mitochondrial trafficking. In contrast to their less-connected vehicle control counterparts, iNet cells remained viable and proliferative after high-dose radiation. These findings demonstrate a link between ROCKi-regulated cell projection dynamics and the formation of radiation-resistant multicellular networks. Our study identifies means to reversibly induce iNet webs ex vivo , and may thereby accelerate future studies into the biology of GBM cellular networks.

Published
2019

46. Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Author

Close, Helen J., primary, Stead, Lucy F., additional, Nsengimana, Jérémie, additional, Reilly, Katrina A., additional, Droop, Alastair, additional, Wurdak, Heiko, additional, Mathew, Ryan K., additional, Corns, Robert, additional, Newton-Bishop, Julia, additional, Melcher, Alan A., additional, Short, Susan C., additional, Cook, Graham P., additional, and Wilson, Erica B., additional

Published
2019
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47. JARID2 facilitates transcriptional reprogramming in glioblastoma in response to standard treatment

Author

Rippaus, Nora, primary, F-Bruns, Alexander, additional, Tanner, Georgette, additional, Taylor, Claire, additional, Droop, Alastair, additional, Brüning-Richardson, Anke, additional, Care, Matthew A., additional, Wilkinson, Joseph, additional, Jenkinson, Michael D., additional, Brodbelt, Andrew, additional, Chakrabarty, Aruna, additional, Ismail, Azzam, additional, Short, Susan, additional, and Stead, Lucy F., additional

Published
2019
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