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2. Engineered CD47 protects T cells for enhanced antitumour immunity

Author

Yamada-Hunter, Sean A., Theruvath, Johanna, McIntosh, Brianna J., Freitas, Katherine A., Lin, Frank, Radosevich, Molly T., Leruste, Amaury, Dhingra, Shaurya, Martinez-Velez, Naiara, Xu, Peng, Huang, Jing, Delaidelli, Alberto, Desai, Moksha H., Good, Zinaida, Polak, Roel, May, Audre, Labanieh, Louai, Bjelajac, Jeremy, Murty, Tara, Ehlinger, Zach, Mount, Christopher W., Chen, Yiyun, Heitzeneder, Sabine, Marjon, Kristopher D., Banuelos, Allison, Khan, Omair, Wasserman, Savannah L., Spiegel, Jay Y., Fernandez-Pol, Sebastian, Kuo, Calvin J., Sorensen, Poul H., Monje, Michelle, Majzner, Robbie G., Weissman, Irving L., Sahaf, Bita, Sotillo, Elena, Cochran, Jennifer R., and Mackall, Crystal L.

Published
2024
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3. A prognostic neural epigenetic signature in high-grade glioma

Author

Drexler, Richard, Khatri, Robin, Sauvigny, Thomas, Mohme, Malte, Maire, Cecile L., Ryba, Alice, Zghaibeh, Yahya, Dührsen, Lasse, Salviano-Silva, Amanda, Lamszus, Katrin, Westphal, Manfred, Gempt, Jens, Wefers, Annika K., Neumann, Julia E., Bode, Helena, Hausmann, Fabian, Huber, Tobias B., Bonn, Stefan, Jütten, Kerstin, Delev, Daniel, Weber, Katharina J., Harter, Patrick N., Onken, Julia, Vajkoczy, Peter, Capper, David, Wiestler, Benedikt, Weller, Michael, Snijder, Berend, Buck, Alicia, Weiss, Tobias, Göller, Pauline C., Sahm, Felix, Menstel, Joelle Aline, Zimmer, David Niklas, Keough, Michael B., Ni, Lijun, Monje, Michelle, Silverbush, Dana, Hovestadt, Volker, Suvà, Mario L., Krishna, Saritha, Hervey-Jumper, Shawn L., Schüller, Ulrich, Heiland, Dieter H., Hänzelmann, Sonja, and Ricklefs, Franz L.

Published
2024
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4. Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas

Author

Bredel, Markus, Espinosa, Lluís, Kim, Hyunsoo, Scholtens, Denise M, McElroy, Joseph P, Rajbhandari, Rajani, Meng, Wei, Kollmeyer, Thomas M, Malta, Tathiane M, Quezada, Michael A, Harsh, Griffith R, Lobo-Jarne, Teresa, Solé, Laura, Merati, Aran, Nagaraja, Surya, Nair, Sindhu, White, Jaclyn J, Thudi, Nanda K, Fleming, Jessica L, Webb, Amy, Natsume, Atsushi, Ogawa, Seishi, Weber, Ruthild G, Bertran, Joan, Haque, S Jaharul, Hentschel, Bettina, Miller, C Ryan, Furnari, Frank B, Chan, Timothy A, Grosu, Anca-Ligia, Weller, Michael, Barnholtz-Sloan, Jill S, Monje, Michelle, Noushmehr, Houtan, Jenkins, Robert B, Rogers, C Leland, MacDonald, David R, Pugh, Stephanie L, and Chakravarti, Arnab

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Orphan Drug, Genetics, Brain Disorders, Brain Cancer, Human Genome, Child, Humans, Brain Neoplasms, Epigenome, Glioma, Haploinsufficiency, Mutation, NF-KappaB Inhibitor alpha, Isocitrate Dehydrogenase, H3K27M mutation, IDH mutation, NFKBIA deletion, glioma, haploinsufficiency, methylome, nomogram, tumor suppressor, Biomedical and clinical sciences
Abstract

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.

Published
2023

5. Glioblastoma remodelling of human neural circuits decreases survival

Author

Krishna, Saritha, Choudhury, Abrar, Keough, Michael B, Seo, Kyounghee, Ni, Lijun, Kakaizada, Sofia, Lee, Anthony, Aabedi, Alexander, Popova, Galina, Lipkin, Benjamin, Cao, Caroline, Nava Gonzales, Cesar, Sudharshan, Rasika, Egladyous, Andrew, Almeida, Nyle, Zhang, Yalan, Molinaro, Annette M, Venkatesh, Humsa S, Daniel, Andy GS, Shamardani, Kiarash, Hyer, Jeanette, Chang, Edward F, Findlay, Anne, Phillips, Joanna J, Nagarajan, Srikantan, Raleigh, David R, Brang, David, Monje, Michelle, and Hervey-Jumper, Shawn L

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Brain Disorders, Cancer, Rare Diseases, Brain Cancer, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Neurological, Humans, Brain, Brain Neoplasms, Glioblastoma, Neural Pathways, Thrombospondin 1, Gabapentin, Disease Progression, Cognition, Survival Rate, Wakefulness, Biopsy, Cell Proliferation, General Science & Technology
Abstract

Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1-4 and gliomas increasing neuronal excitability2,5-8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.

Published
2023

7. Glioma synapses recruit mechanisms of adaptive plasticity

Author

Taylor, Kathryn R., Barron, Tara, Hui, Alexa, Spitzer, Avishay, Yalçin, Belgin, Ivec, Alexis E., Geraghty, Anna C., Hartmann, Griffin G., Arzt, Marlene, Gillespie, Shawn M., Kim, Yoon Seok, Maleki Jahan, Samin, Zhang, Helena, Shamardani, Kiarash, Su, Minhui, Ni, Lijun, Du, Peter P., Woo, Pamelyn J., Silva-Torres, Arianna, Venkatesh, Humsa S., Mancusi, Rebecca, Ponnuswami, Anitha, Mulinyawe, Sara, Keough, Michael B., Chau, Isabelle, Aziz-Bose, Razina, Tirosh, Itay, Suvà, Mario L., and Monje, Michelle

Published
2023
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8. Distinguishing features of long COVID identified through immune profiling

Author

Klein, Jon, Wood, Jamie, Jaycox, Jillian R., Dhodapkar, Rahul M., Lu, Peiwen, Gehlhausen, Jeff R., Tabachnikova, Alexandra, Greene, Kerrie, Tabacof, Laura, Malik, Amyn A., Silva Monteiro, Valter, Silva, Julio, Kamath, Kathy, Zhang, Minlu, Dhal, Abhilash, Ott, Isabel M., Valle, Gabrielee, Peña-Hernández, Mario, Mao, Tianyang, Bhattacharjee, Bornali, Takahashi, Takehiro, Lucas, Carolina, Song, Eric, McCarthy, Dayna, Breyman, Erica, Tosto-Mancuso, Jenna, Dai, Yile, Perotti, Emily, Akduman, Koray, Tzeng, Tiffany J., Xu, Lan, Geraghty, Anna C., Monje, Michelle, Yildirim, Inci, Shon, John, Medzhitov, Ruslan, Lutchmansingh, Denyse, Possick, Jennifer D., Kaminski, Naftali, Omer, Saad B., Krumholz, Harlan M., Guan, Leying, Dela Cruz, Charles S., van Dijk, David, Ring, Aaron M., Putrino, David, and Iwasaki, Akiko

Published
2023
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9. Microglia states and nomenclature: A field at its crossroads

Author

Paolicelli, Rosa C, Sierra, Amanda, Stevens, Beth, Tremblay, Marie-Eve, Aguzzi, Adriano, Ajami, Bahareh, Amit, Ido, Audinat, Etienne, Bechmann, Ingo, Bennett, Mariko, Bennett, Frederick, Bessis, Alain, Biber, Knut, Bilbo, Staci, Blurton-Jones, Mathew, Boddeke, Erik, Brites, Dora, Brône, Bert, Brown, Guy C, Butovsky, Oleg, Carson, Monica J, Castellano, Bernardo, Colonna, Marco, Cowley, Sally A, Cunningham, Colm, Davalos, Dimitrios, De Jager, Philip L, de Strooper, Bart, Denes, Adam, Eggen, Bart JL, Eyo, Ukpong, Galea, Elena, Garel, Sonia, Ginhoux, Florent, Glass, Christopher K, Gokce, Ozgun, Gomez-Nicola, Diego, González, Berta, Gordon, Siamon, Graeber, Manuel B, Greenhalgh, Andrew D, Gressens, Pierre, Greter, Melanie, Gutmann, David H, Haass, Christian, Heneka, Michael T, Heppner, Frank L, Hong, Soyon, Hume, David A, Jung, Steffen, Kettenmann, Helmut, Kipnis, Jonathan, Koyama, Ryuta, Lemke, Greg, Lynch, Marina, Majewska, Ania, Malcangio, Marzia, Malm, Tarja, Mancuso, Renzo, Masuda, Takahiro, Matteoli, Michela, McColl, Barry W, Miron, Veronique E, Molofsky, Anna Victoria, Monje, Michelle, Mracsko, Eva, Nadjar, Agnes, Neher, Jonas J, Neniskyte, Urte, Neumann, Harald, Noda, Mami, Peng, Bo, Peri, Francesca, Perry, V Hugh, Popovich, Phillip G, Pridans, Clare, Priller, Josef, Prinz, Marco, Ragozzino, Davide, Ransohoff, Richard M, Salter, Michael W, Schaefer, Anne, Schafer, Dorothy P, Schwartz, Michal, Simons, Mikael, Smith, Cody J, Streit, Wolfgang J, Tay, Tuan Leng, Tsai, Li-Huei, Verkhratsky, Alexei, von Bernhardi, Rommy, Wake, Hiroaki, Wittamer, Valérie, Wolf, Susanne A, Wu, Long-Jun, and Wyss-Coray, Tony

Subjects
Microglia, Neurosciences, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.

Published
2022

10. Remote neuronal activity drives glioma progression through SEMA4F

Author

Huang-Hobbs, Emmet, Cheng, Yi-Ting, Ko, Yeunjung, Luna-Figueroa, Estefania, Lozzi, Brittney, Taylor, Kathryn R., McDonald, Malcolm, He, Peihao, Chen, Hsiao-Chi, Yang, Yuhui, Maleki, Ehson, Lee, Zhung-Fu, Murali, Sanjana, Williamson, Michael R., Choi, Dongjoo, Curry, Rachel, Bayley, James, Woo, Junsung, Jalali, Ali, Monje, Michelle, Noebels, Jeffrey L., Harmanci, Akdes Serin, Rao, Ganesh, and Deneen, Benjamin

Published
2023
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11. Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication

Author

Theruvath, Johanna, Menard, Marie, Smith, Benjamin AH, Linde, Miles H, Coles, Garry L, Dalton, Guillermo Nicolas, Wu, Wei, Kiru, Louise, Delaidelli, Alberto, Sotillo, Elena, Silberstein, John L, Geraghty, Anna C, Banuelos, Allison, Radosevich, Molly Thomas, Dhingra, Shaurya, Heitzeneder, Sabine, Tousley, Aidan, Lattin, John, Xu, Peng, Huang, Jing, Nasholm, Nicole, He, Andy, Kuo, Tracy C, Sangalang, Emma RB, Pons, Jaume, Barkal, Amira, Brewer, Rachel E, Marjon, Kristopher D, Vilches-Moure, Jose G, Marshall, Payton L, Fernandes, Ricardo, Monje, Michelle, Cochran, Jennifer R, Sorensen, Poul H, Daldrup-Link, Heike E, Weissman, Irving L, Sage, Julien, Majeti, Ravindra, Bertozzi, Carolyn R, Weiss, William A, Mackall, Crystal L, and Majzner, Robbie G

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Pediatric Research Initiative, Pediatric, Neurosciences, Pediatric Cancer, Rare Diseases, Orphan Drug, Cancer, Neuroblastoma, Animals, Bone Neoplasms, CD47 Antigen, Cell Line, Tumor, Humans, Immunotherapy, Mice, Neoplasm Recurrence, Local, Phagocytosis, Tumor Microenvironment, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2+ malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.

Published
2022

12. Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer’s model

Author

Reinitz, Felicia, Chen, Elizabeth Y, di Robilant, Benedetta Nicolis, Chuluun, Bayarsaikhan, Antony, Jane, Jones, Robert C, Gubbi, Neha, Lee, Karen, Ho, William Hai Dang, Kolluru, Sai Saroja, Qian, Dalong, Adorno, Maddalena, Piltti, Katja, Anderson, Aileen, Monje, Michelle, Heller, H Craig, Quake, Stephen R, and Clarke, Michael F

Subjects
Biochemistry and Cell Biology, Biological Sciences, Regenerative Medicine, Genetics, Stem Cell Research, Alzheimer's Disease, Neurosciences, Neurodegenerative, Acquired Cognitive Impairment, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Cellular Senescence, Disease Models, Animal, Inflammation, Mice, Mice, Transgenic, Neurodegenerative Diseases, Plaque, Amyloid, Ubiquitin Thiolesterase, neural stem cells, Alzheimer's, neurodegeneration, Mouse, mouse, regenerative medicine, stem cells, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.

Published
2022

13. Tumor inflammation-associated neurotoxicity

Author

Mahdi, Jasia, Dietrich, Jorg, Straathof, Karin, Roddie, Claire, Scott, Brian J., Davidson, Tom Belle, Prolo, Laura M., Batchelor, Tracy T., Campen, Cynthia J., Davis, Kara L., Gust, Juliane, Lim, Michael, Majzner, Robbie G., Park, Julie R., Partap, Sonia, Ramakrishna, Sneha, Richards, Rebecca, Schultz, Liora, Vitanza, Nicholas A., Wang, Leo D., Mackall, Crystal L., and Monje, Michelle

Published
2023
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14. NF1 mutation drives neuronal activity-dependent initiation of optic glioma

Author

Pan, Yuan, Hysinger, Jared D, Barron, Tara, Schindler, Nicki F, Cobb, Olivia, Guo, Xiaofan, Yalçın, Belgin, Anastasaki, Corina, Mulinyawe, Sara B, Ponnuswami, Anitha, Scheaffer, Suzanne, Ma, Yu, Chang, Kun-Che, Xia, Xin, Toonen, Joseph A, Lennon, James J, Gibson, Erin M, Huguenard, John R, Liau, Linda M, Goldberg, Jeffrey L, Monje, Michelle, and Gutmann, David H

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Neurofibromatosis, Brain Disorders, Rare Diseases, Cancer, Stem Cell Research - Nonembryonic - Non-Human, Genetics, Eye Disease and Disorders of Vision, Stem Cell Research, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Animals, Astrocytoma, Cell Adhesion Molecules, Neuronal, Cell Transformation, Neoplastic, Female, Genes, Neurofibromatosis 1, Germ-Line Mutation, Humans, Male, Membrane Proteins, Mice, Mutation, Nerve Tissue Proteins, Neurofibromin 1, Neurons, Optic Nerve, Optic Nerve Glioma, Photic Stimulation, Retina, General Science & Technology
Abstract

Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising  the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.

Published
2021

16. The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location

Author

Liu, Ilon, Jiang, Li, Samuelsson, Erik R., Marco Salas, Sergio, Beck, Alexander, Hack, Olivia A., Jeong, Daeun, Shaw, McKenzie L., Englinger, Bernhard, LaBelle, Jenna, Mire, Hafsa M., Madlener, Sibylle, Mayr, Lisa, Quezada, Michael A., Trissal, Maria, Panditharatna, Eshini, Ernst, Kati J., Vogelzang, Jayne, Gatesman, Taylor A., Halbert, Matthew E., Palova, Hana, Pokorna, Petra, Sterba, Jaroslav, Slaby, Ondrej, Geyeregger, Rene, Diaz, Aaron, Findlay, Izac J., Dun, Matthew D., Resnick, Adam, Suvà, Mario L., Jones, David T. W., Agnihotri, Sameer, Svedlund, Jessica, Koschmann, Carl, Haberler, Christine, Czech, Thomas, Slavc, Irene, Cotter, Jennifer A., Ligon, Keith L., Alexandrescu, Sanda, Yung, W. K. Alfred, Arrillaga-Romany, Isabel, Gojo, Johannes, Monje, Michelle, Nilsson, Mats, and Filbin, Mariella G.

Published
2022
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18. Immunotherapy-related cognitive impairment after CAR T cell therapy in mice

Author

Geraghty, Anna C, primary, Acosta-Alvarez, Lehi, additional, Rotiroti, Maria C, additional, Dutton, Selena, additional, O'Dea, Michael, additional, Woo, Pamelyn, additional, Xu, Haojun, additional, Shamardani, Kiarash, additional, Mancusi, Rebecca, additional, Ni, Lijun, additional, Mulinyawe, Sara B, additional, Kim, Won Ju, additional, Liddelow, Shane, additional, Majzner, Robbie G, additional, and Monje, Michelle, additional

Published
2024
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19. CRISPRi-based radiation modifier screen identifies long non-coding RNA therapeutic targets in glioma

Author

Liu, S John, Malatesta, Martina, Lien, Brian V, Saha, Parna, Thombare, Shivani S, Hong, Sung Jun, Pedraza, Leslie, Koontz, Mark, Seo, Kyounghee, Horlbeck, Max A, He, Daniel, Birk, Harjus S, Jain, Miten, Olsen, Hugh E, Akeson, Mark, Weissman, Jonathan S, Monje, Michelle, Gupta, Nalin, Raleigh, David R, Ullian, Erik M, and Lim, Daniel A

Subjects
Biomedical and Clinical Sciences, Medicinal and Biomolecular Chemistry, Chemical Sciences, Oncology and Carcinogenesis, Genetics, Rare Diseases, Pediatric, Brain Disorders, Neurosciences, Orphan Drug, Brain Cancer, Biotechnology, Cancer, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Adult, Astrocytes, Brain, Brain Neoplasms, CRISPR-Cas Systems, Cell Line, Tumor, Combined Modality Therapy, Glioblastoma, Humans, Oligonucleotides, Antisense, Organoids, RNA, Long Noncoding, Radiation Tolerance, CRISPRi, lncRNA, Radiation, Glioma, Cancer therapy, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Bioinformatics
Abstract

BackgroundLong non-coding RNAs (lncRNAs) exhibit highly cell type-specific expression and function, making this class of transcript attractive for targeted cancer therapy. However, the vast majority of lncRNAs have not been tested as potential therapeutic targets, particularly in the context of currently used cancer treatments. Malignant glioma is rapidly fatal, and ionizing radiation is part of the current standard-of-care used to slow tumor growth in both adult and pediatric patients.ResultsWe use CRISPR interference (CRISPRi) to screen 5689 lncRNA loci in human glioblastoma (GBM) cells, identifying 467 hits that modify cell growth in the presence of clinically relevant doses of fractionated radiation. Thirty-three of these lncRNA hits sensitize cells to radiation, and based on their expression in adult and pediatric gliomas, nine of these hits are prioritized as lncRNA Glioma Radiation Sensitizers (lncGRS). Knockdown of lncGRS-1, a primate-conserved, nuclear-enriched lncRNA, inhibits the growth and proliferation of primary adult and pediatric glioma cells, but not the viability of normal brain cells. Using human brain organoids comprised of mature neural cell types as a three-dimensional tissue substrate to model the invasive growth of glioma, we find that antisense oligonucleotides targeting lncGRS-1 selectively decrease tumor growth and sensitize glioma cells to radiation therapy.ConclusionsThese studies identify lncGRS-1 as a glioma-specific therapeutic target and establish a generalizable approach to rapidly identify novel therapeutic targets in the vast non-coding genome to enhance radiation therapy.

Published
2020

20. Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG

Author

Balakrishnan, Ilango, Danis, Etienne, Pierce, Angela, Madhavan, Krishna, Wang, Dong, Dahl, Nathan, Sanford, Bridget, Birks, Diane K, Davidson, Nate, Metselaar, Dennis S, Meel, Michaël Hananja, Lemma, Rakeb, Donson, Andrew, Vijmasi, Trinka, Katagi, Hiroaki, Sola, Ismail, Fosmire, Susan, Alimova, Irina, Steiner, Jenna, Gilani, Ahmed, Hulleman, Esther, Serkova, Natalie J, Hashizume, Rintaro, Hawkins, Cynthia, Carcaboso, Angel M, Gupta, Nalin, Monje, Michelle, Jabado, Nada, Jones, Kenneth, Foreman, Nicholas, Green, Adam, Vibhakar, Rajeev, and Venkataraman, Sujatha

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Genetics, Stem Cell Research, Biotechnology, Cancer, Brain Disorders, Stem Cell Research - Nonembryonic - Non-Human, Brain Cancer, Aging, Astrocytoma, Brain Stem Neoplasms, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Child, Child, Preschool, Chromatin, Diffuse Intrinsic Pontine Glioma, Epigenomics, Female, Glioma, Histones, Humans, Lysine, Male, Mutation, Neoplasm Recurrence, Local, Polycomb Repressive Complex 1, BH3 mimetics, BMI1, DIPG, H3K27M mutant, H3WT, PTC 028, RNAi screen, SASP, senescence, Bmi1, PTC028, Medical Physiology, Biological sciences
Abstract

Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.

Published
2020

21. Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1

Author

Mabe, Nathaniel W., Huang, Min, Dalton, Guillermo N., Alexe, Gabriela, Schaefer, Daniel A., Geraghty, Anna C., Robichaud, Amanda L., Conway, Amy S., Khalid, Delan, Mader, Marius M., Belk, Julia A., Ross, Kenneth N., Sheffer, Michal, Linde, Miles H., Ly, Nghi, Yao, Winnie, Rotiroti, Maria Caterina, Smith, Benjamin A. H., Wernig, Marius, Bertozzi, Carolyn R., Monje, Michelle, Mitsiades, Constantine S., Majeti, Ravindra, Satpathy, Ansuman T., Stegmaier, Kimberly, and Majzner, Robbie G.

Published
2022
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22. Cancer neuroscience: State of the field, emerging directions

Author

Winkler, Frank, Venkatesh, Humsa S., Amit, Moran, Batchelor, Tracy, Demir, Ihsan Ekin, Deneen, Benjamin, Gutmann, David H., Hervey-Jumper, Shawn, Kuner, Thomas, Mabbott, Donald, Platten, Michael, Rolls, Asya, Sloan, Erica K., Wang, Timothy C., Wick, Wolfgang, Venkataramani, Varun, and Monje, Michelle

Published
2023
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23. Generation and multi-dimensional profiling of a childhood cancer cell line atlas defines new therapeutic opportunities

Author

Sun, Claire Xin, Daniel, Paul, Bradshaw, Gabrielle, Shi, Hui, Loi, Melissa, Chew, Nicole, Parackal, Sarah, Tsui, Vanessa, Liang, Yuqing, Koptyra, Mateusz, Adjumain, Shazia, Sun, Christie, Chong, Wai Chin, Fernando, Dasun, Drinkwater, Caroline, Tourchi, Motahhareh, Habarakada, Dilru, Sooraj, Dhanya, Carvalho, Diana, Storm, Phillip B., Baubet, Valerie, Sayles, Leanne C., Fernandez, Elisabet, Nguyen, Thy, Pörksen, Mia, Doan, Anh, Crombie, Duncan E., Panday, Monty, Zhukova, Nataliya, Dun, Matthew D., Ludlow, Louise E., Day, Bryan, Stringer, Brett W., Neeman, Naama, Rubens, Jeffrey A., Raabe, Eric H., Vinci, Maria, Tyrrell, Vanessa, Fletcher, Jamie I., Ekert, Paul G., Dumevska, Biljana, Ziegler, David S., Tsoli, Maria, Syed Sulaiman, Nur Farhana, Loh, Amos Hong Pheng, Low, Sharon Yin Yee, Sweet-Cordero, E. Alejandro, Monje, Michelle, Resnick, Adam, Jones, Chris, Downie, Peter, Williams, Bryan, Rosenbluh, Joseph, Gough, Daniel, Cain, Jason E., and Firestein, Ron

Published
2023
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24. Roadmap for the Emerging Field of Cancer Neuroscience.

Author

Monje, Michelle, Borniger, Jeremy, DSilva, Nisha, Deneen, Benjamin, Dirks, Peter, Fattahi, Faranak, Frenette, Paul, Garzia, Livia, Gutmann, David, Hanahan, Douglas, Hervey-Jumper, Shawn, Hondermarck, Hubert, Hurov, Jonathan, Kepecs, Adam, Lloyd, Alison, Magnon, Claire, Saloman, Jami, Segal, Rosalind, Sloan, Erica, Sun, Xin, Taylor, Michael, Tracey, Kevin, Trotman, Lloyd, Tuveson, David, Wang, Timothy, White, Ruth, Winkler, Frank, and Knox, Sarah

Subjects
Humans, Neoplasms, Nervous System, Neurosciences
Abstract

Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of cancer neuroscience and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.

Published
2020

25. NCI-CONNECT: Comprehensive Oncology Network Evaluating Rare CNS Tumors-Histone Mutated Midline Glioma Workshop Proceedings.

Author

Theeler, Brett J, Dalal, Yamini, Monje, Michelle, Shilatifard, Ali, Suvà, Mario L, Aboud, Orwa, Camphausen, Kevin, Cordova, Christine, Finch, Elizabeth, Heiss, John D, Packer, Roger J, Romo, Carlos G, Aldape, Kenneth, Penas-Prado, Marta, Armstrong, Terri, and Gilbert, Mark R

Subjects
NCI-CONNECT, clinical trials, histone-mutated glioma, rare brain tumors, Pediatric, Rare Diseases, Brain Cancer, Brain Disorders, Neurosciences, Orphan Drug, Genetics, Pediatric Cancer, Cancer
Abstract

Histone mutations occur in approximately 4% of different cancer types. In 2012, mutations were found in the gene encoding histone variant H3.3 (H3F3A gene) in pediatric diffuse intrinsic pontine gliomas and pediatric hemispheric gliomas. Tumors with mutations in the H3F3A gene are generally characterized as histone mutated gliomas (HMGs) or diffuse midline gliomas. HMGs are a rare subtype of glial tumor that is malignant and fast growing, carrying a poor prognosis. In 2017, the Beau Biden Cancer Moonshot Program appropriated $1.7 billion toward cancer care in 10 select areas. The National Cancer Institute (NCI) was granted support to focus specifically on rare central nervous system (CNS) tumors through NCI-CONNECT. Its mission is to address the challenges and unmet needs in CNS cancer research and treatment by connecting patients, providers, researchers, and advocacy organizations to work in partnership. On September 27, 2018, NCI-CONNECT convened a workshop on histone mutated midline glioma, one of the 12 CNS cancers included in its initial portfolio. Three leaders in the field provided an overview of advances in histone mutated midline glioma research. These experts shared observations and experiences related to common scientific and clinical challenges in studying these tumors. Although the clinical focus of this workshop was on adult patients, one important objective was to start a collaborative dialogue between pediatric and adult clinicians and researchers. Meeting participants identified needs for diagnostic and treatment standards, disease biology and biological targets for this cancer, disease-specific trial designs, and developed a list of action items and future direction.

Published
2020

28. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas

Author

Majzner, Robbie G., Ramakrishna, Sneha, Yeom, Kristen W., Patel, Shabnum, Chinnasamy, Harshini, Schultz, Liora M., Richards, Rebecca M., Jiang, Li, Barsan, Valentin, Mancusi, Rebecca, Geraghty, Anna C., Good, Zinaida, Mochizuki, Aaron Y., Gillespie, Shawn M., Toland, Angus Martin Shaw, Mahdi, Jasia, Reschke, Agnes, Nie, Esther H., Chau, Isabelle J., Rotiroti, Maria Caterina, Mount, Christopher W., Baggott, Christina, Mavroukakis, Sharon, Egeler, Emily, Moon, Jennifer, Erickson, Courtney, Green, Sean, Kunicki, Michael, Fujimoto, Michelle, Ehlinger, Zach, Reynolds, Warren, Kurra, Sreevidya, Warren, Katherine E., Prabhu, Snehit, Vogel, Hannes, Rasmussen, Lindsey, Cornell, Timothy T., Partap, Sonia, Fisher, Paul G., Campen, Cynthia J., Filbin, Mariella G., Grant, Gerald, Sahaf, Bita, Davis, Kara L., Feldman, Steven A., Mackall, Crystal L., and Monje, Michelle

Published
2022
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29. Tackling Brain and Muscle Dysfunction in Acute Respiratory Distress Syndrome Survivors: NHLBI Workshop Report.

Author

Palakshappa, Jessica A., Batt, Jane A. E., Bodine, Sue C., Connolly, Bronwen A., Doles, Jason, Falvey, Jason R., Ferrante, Lauren E., Files, D. Clark, Harhay, Michael O., Harrell, Kirsten, Hippensteel, Joseph A., Iwashyna, Theodore J., Jackson, James C., Lane-Fall, Meghan B., Monje, Michelle, Moss, Marc, Needham, Dale M., Semler, Matthew W., Lahiri, Shouri, and Larsson, Lars

Subjects
ADULT respiratory distress syndrome, RESPIRATORY distress syndrome
Abstract

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproved. The NHLBI of the NIH assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and well-being of ARDS survivors. [ABSTRACT FROM AUTHOR]

Published
2024
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31. MODL-07. NF1 MUTATION IN OLIGODENDROCYTE PRECURSOR CELLS INDUCES PRENEOPLASTIC LESIONS IN THE BRAIN

Author

Pan, Yuan, primary, Hysinger, Jared, additional, Yalçın, Belgin, additional, Lennon, James, additional, Raghavan, Preethi, additional, Schindler, Nicole, additional, Anastasaki, Corina, additional, Chatterjee, Jit, additional, Mount, Christopher, additional, Nagaraja, Surya, additional, Scheaffer, Suzanne, additional, Attardi, Laura, additional, Gutmann, David, additional, and Monje, Michelle, additional

Published
2023
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32. CNSC-25. NEURAL SIGNATURE OF GBM EXHIBITS SYNAPTOGENIC AND OPC-LIKE FEATURES AND INDEPENDENTLY PREDICTS PATIENT SURVIVAL

Author

Drexler, Richard, primary, Khatri, Robin, additional, Sauvigny, Thomas, additional, Mohme, Malte, additional, Ryba, Alice, additional, Dührsen, Lasse, additional, Maire, Cecile, additional, Salviano-Silva, Amanda, additional, Lamszus, Katrin, additional, Westphal, Manfred, additional, Gempt, Jens, additional, Wefers, Annika, additional, Neumann, Julia, additional, Bode, Helena, additional, Hausmann, Fabian, additional, Huber, Tobias, additional, Bonn, Stefan, additional, Delev, Daniel, additional, Weber, Katharina, additional, Harter, Patrick, additional, Onken, Julia, additional, Vajkoczy, Peter, additional, Capper, David, additional, Wiestler, Benedikt, additional, Monje, Michelle, additional, Silverbush, Dana, additional, Hovestadt, Volker, additional, Suva, Mario, additional, Krishna, Saritha, additional, Hervey-Jumper, Shawn, additional, Schüller, Ulrich, additional, Heiland, Dieter Henrik, additional, Hänzelmann, Sonja, additional, and Ricklefs, Franz L, additional

Published
2023
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33. Pediatric high-grade glioma: biologically and clinically in need of new thinking.

Author

Jones, Chris, Karajannis, Matthias A, Jones, David TW, Kieran, Mark W, Monje, Michelle, Baker, Suzanne J, Becher, Oren J, Cho, Yoon-Jae, Gupta, Nalin, Hawkins, Cynthia, Hargrave, Darren, Haas-Kogan, Daphne A, Jabado, Nada, Li, Xiao-Nan, Mueller, Sabine, Nicolaides, Theo, Packer, Roger J, Persson, Anders I, Phillips, Joanna J, Simonds, Erin F, Stafford, James M, Tang, Yujie, Pfister, Stefan M, and Weiss, William A

Subjects
Humans, Glioma, Brain Neoplasms, Cell Transformation, Neoplastic, Prognosis, Child, Neoplasm Grading, DIPG, clinical trials, genomics, glioma, pediatric, Clinical Trials and Supportive Activities, Rare Diseases, Brain Cancer, Neurosciences, Brain Disorders, Pediatric, Cancer, Clinical Research, Orphan Drug, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and suggests approaches for innovative clinical management.

Published
2017

34. Patient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma

Author

He, Chen, Xu, Ke, Zhu, Xiaoyan, Dunphy, Paige S., Gudenas, Brian, Lin, Wenwei, Twarog, Nathaniel, Hover, Laura D., Kwon, Chang-Hyuk, Kasper, Lawryn H., Zhang, Junyuan, Li, Xiaoyu, Dalton, James, Jonchere, Barbara, Mercer, Kimberly S., Currier, Duane G., Caufield, William, Wang, Yingzhe, Xie, Jia, Broniscer, Alberto, Wetmore, Cynthia, Upadhyaya, Santhosh A., Qaddoumi, Ibrahim, Klimo, Paul, Boop, Frederick, Gajjar, Amar, Zhang, Jinghui, Orr, Brent A., Robinson, Giles W., Monje, Michelle, Freeman III, Burgess B., Roussel, Martine F., Northcott, Paul A., Chen, Taosheng, Rankovic, Zoran, Wu, Gang, Chiang, Jason, Tinkle, Christopher L., Shelat, Anang A., and Baker, Suzanne J.

Published
2021
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35. A combined immunopeptidomics, proteomics, and cell surface proteomics approach to identify immunotherapy targets for diffuse intrinsic pontine glioma

Author

Pandey, Kirti, primary, Wang, Stacie S., additional, Mifsud, Nicole A., additional, Faridi, Pouya, additional, Davenport, Alexander J., additional, Webb, Andrew I., additional, Sandow, Jarrod J., additional, Ayala, Rochelle, additional, Monje, Michelle, additional, Cross, Ryan S., additional, Ramarathinam, Sri H., additional, Jenkins, Misty R., additional, and Purcell, Anthony W., additional

Published
2023
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36. Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability

Author

Drexler, Richard, primary, Khatri, Robin, additional, Sauvigny, Thomas, additional, Mohme, Malte, additional, Maire, Cecile L., additional, Ryba, Alice, additional, Zghaibeh, Yahya, additional, Dührsen, Lasse, additional, Salviano-Silva, Amanda, additional, Lamszus, Katrin, additional, Westphal, Manfred, additional, Gempt, Jens, additional, Wefers, Annika K., additional, Neumann, Julia, additional, Bode, Helena, additional, Hausmann, Fabian, additional, Huber, Tobias B., additional, Bonn, Stefan, additional, Jütten, Kerstin, additional, Delev, Daniel, additional, Weber, Katharina J., additional, Harter, Patrick N., additional, Onken, Julia, additional, Vajkoczy, Peter, additional, Capper, David, additional, Wiestler, Benedikt, additional, Weller, Michael, additional, Snijder, Berend, additional, Buck, Alicia, additional, Weiss, Tobias, additional, Keough, Michael B., additional, Ni, Lijun, additional, Monje, Michelle, additional, Silverbush, Dana, additional, Hovestadt, Volker, additional, Suvà, Mario L., additional, Krishna, Saritha, additional, Hervey-Jumper, Shawn L., additional, Schüller, Ulrich, additional, Heiland, Dieter H., additional, Hänzelmann, Sonja, additional, and Ricklefs, Franz L., additional

Published
2023
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38. Phase I trial of panobinostat in children with diffuse intrinsic pontine glioma: A report from the Pediatric Brain Tumor Consortium (PBTC-047)

Author

Monje, Michelle, primary, Cooney, Tabitha, additional, Glod, John, additional, Huang, Jie, additional, Peer, Cody J, additional, Faury, Damien, additional, Baxter, Patricia, additional, Kramer, Kim, additional, Lenzen, Alicia, additional, Robison, Nathan J, additional, Kilburn, Lindsay, additional, Vinitsky, Anna, additional, Figg, William D, additional, Jabado, Nada, additional, Fouladi, Maryam, additional, Fangusaro, Jason, additional, Onar-Thomas, Arzu, additional, Dunkel, Ira J, additional, and Warren, Katherine E, additional

Published
2023
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39. SYST-15 GENERATION AND MULTI-DIMENSIONAL PROFILING OF A CHILDHOOD CANCER CELL LINE ATLAS DEFINES NEW THERAPEUTIC OPPORTUNITIES

Author

Daniel, Paul, primary, Sun, Claire Xin, additional, Bradshaw, Gabrielle, additional, Shi, Hui, additional, Loi, Melissa, additional, Chew, Nicole, additional, Parackal, Sarah, additional, Tsui, Vanessa, additional, Liang, Yuqing, additional, Koptyra, Mateusz, additional, Adjumain, Shazia, additional, Sun, Christie, additional, Chong, Wai Chin, additional, Fernando, Dasun, additional, Drinkwater, Caroline, additional, Tourchi, Motahhareh, additional, Habarakada, Dilru, additional, Carvalho, Diana, additional, Storm, Phillip B, additional, Baubet, Valerie, additional, Sayles, Leanne C, additional, Fernandez, Elisabet, additional, Zhukova, Nataliya, additional, Dun, Matthew D, additional, Ludlow, Louise E, additional, Day, Bryan, additional, Stringer, Brett W, additional, Neeman, Naama, additional, Rubens, Jeffrey A, additional, Raabe, Eric H, additional, Vinci, Maria, additional, Tyrrell, Vanessa, additional, Fletcher, Jamie I, additional, Ekert, Paul G, additional, Dumevska, Biljana, additional, Ziegler, David S, additional, Tsoli, Maria, additional, Sulaiman, Nur Farhana Syed, additional, Loh, Amos Hong Pheng, additional, Low, Sharon Yin Yee, additional, Sweet-Cordero, E Alejandro, additional, Monje, Michelle, additional, Resnick, Adam, additional, Jones, Chris, additional, Downie, Peter, additional, Williams, Bryan, additional, Rosenbluh, Joseph, additional, Gough, Daniel, additional, Cain, Jason E, additional, and Firestein, Ron, additional

Published
2023
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40. Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors

Author

Theruvath, Johanna, Sotillo, Elena, Mount, Christopher W., Graef, Claus Moritz, Delaidelli, Alberto, Heitzeneder, Sabine, Labanieh, Louai, Dhingra, Shaurya, Leruste, Amaury, Majzner, Robbie G., Xu, Peng, Mueller, Sabine, Yecies, Derek W., Finetti, Martina A., Williamson, Daniel, Johann, Pascal D., Kool, Marcel, Pfister, Stefan, Hasselblatt, Martin, Fruhwald, Michael C., Delattre, Olivier, Surdez, Didier, Bourdeaut, Franck, Puget, Stephanie, Zaidi, Sakina, Mitra, Siddhartha S., Cheshier, Samuel, Sorensen, Poul H., Monje, Michelle, and Mackall, Crystal L.

Subjects
T cells -- Health aspects -- Methods, Cellular therapy -- Methods -- Health aspects, Nervous system tumors -- Care and treatment, Antigens -- Health aspects -- Methods, Tumors in children -- Care and treatment, Biological sciences, Health
Abstract

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months.sup.1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. .sup.3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT.sup.5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies. CAR T cells administered intracerebroventricularly or intratumorally exhibit more rapid kinetics, reduced systemic toxicity and greater therapeutic potency as compared to intravenously delivered CAR T cells in atypical teratoid/rhabdoid tumor xenograft mouse models., Author(s): Johanna Theruvath [sup.1] , Elena Sotillo [sup.1] , Christopher W. Mount [sup.2] , Claus Moritz Graef [sup.1] , Alberto Delaidelli [sup.3] , Sabine Heitzeneder [sup.1] , Louai Labanieh [sup.1] [...]

Published
2020
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41. c-Jun overexpression in CAR T cells induces exhaustion resistance

Author

Lynn, Rachel C., Weber, Evan W., Sotillo, Elena, Gennert, David, Xu, Peng, Good, Zinaida, Anbunathan, Hima, Lattin, John, Jones, Robert, Tieu, Victor, Nagaraja, Surya, Granja, Jeffrey, de Bourcy, Charles F. A., Majzner, Robbie, Satpathy, Ansuman T., Quake, Stephen R., Monje, Michelle, Chang, Howard Y., and Mackall, Crystal L.

Published
2019
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42. Electrical and synaptic integration of glioma into neural circuits

Author

Venkatesh, Humsa S., Morishita, Wade, Geraghty, Anna C., Silverbush, Dana, Gillespie, Shawn M., Arzt, Marlene, Tam, Lydia T., Espenel, Cedric, Ponnuswami, Anitha, Ni, Lijun, Woo, Pamelyn J., Taylor, Kathryn R., Agarwal, Amit, Regev, Aviv, Brang, David, Vogel, Hannes, Hervey-Jumper, Shawn, Bergles, Dwight E., Suvà, Mario L., Malenka, Robert C., and Monje, Michelle

Published
2019
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43. Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition.

Author

Tang, Yujie, Gholamin, Sharareh, Schubert, Simone, Willardson, Minde I, Lee, Alex, Bandopadhayay, Pratiti, Bergthold, Guillame, Masoud, Sabran, Nguyen, Brian, Vue, Nujsaubnusi, Balansay, Brianna, Yu, Furong, Oh, Sekyung, Woo, Pamelyn, Chen, Spenser, Ponnuswami, Anitha, Monje, Michelle, Atwood, Scott X, Whitson, Ramon J, Mitra, Siddhartha, Cheshier, Samuel H, Qi, Jun, Beroukhim, Rameen, Tang, Jean Y, Wechsler-Reya, Rob, Oro, Anthony E, Link, Brian A, Bradner, James E, and Cho, Yoon-Jae

Subjects
Animals, Mice, Neoplasms, Experimental, Azepines, Triazoles, Nuclear Proteins, Transcription Factors, Ligands, Signal Transduction, Transcription, Genetic, Epigenesis, Genetic, Kruppel-Like Transcription Factors, Hedgehog Proteins, Promoter Regions, Genetic, Zinc Finger Protein GLI1, Zinc Finger Protein Gli2, Immunology, Medical and Health Sciences
Abstract

Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.

Published
2014

44. DIPG-19. BAF COMPLEX PERTURBATION AS A NOVEL THERAPEUTIC OPPORTUNITY IN H3K27M PEDIATRIC GLIOMA

Author

Panditharatna, Eshini, primary, Marques, Joana G, additional, Wang, Tingjian, additional, Trissal, Maria, additional, Liu, Ilon, additional, Jiang, Li, additional, Beck, Alexander, additional, Groves, Andrew, additional, Dharia, Neekesh, additional, Hoffman, Samantha, additional, Kugener, Guillaume, additional, Shaw, McKenzie, additional, Hack, Olivia, additional, Dempster, Joshua, additional, Lareau, Caleb, additional, Quezada, Michael, additional, Stanton, Ann-Catherine, additional, Wyatt, Meghan, additional, Kalani, Zohra, additional, Goodale, Amy, additional, Vazquez, Francisca, additional, Piccioni, Federica, additional, Doench, John, additional, Root, David, additional, Anastas, Jamie, additional, Jones, Kristen, additional, Conway, Amy, additional, Stopka, Sylwia, additional, Regan, Michael, additional, Liang, Yu, additional, Seo, Hyuk-Soo, additional, Song, Kijun, additional, Bashyal, Puspalata, additional, Mathewson, Nathan, additional, Dhe-Paganon, Sirano, additional, Suvà, Mario L, additional, Carcaboso, Angel M, additional, Lavarino, Cinzia, additional, Mora, Jaume, additional, Nguyen, Quang-De, additional, Ligon, Keith L, additional, Shi, Yang, additional, Agnihotri, Sameer, additional, Agar, Nathalie Y R, additional, Stegmaier, Kimberly, additional, Stiles, Charles D, additional, Monje, Michelle, additional, Golub, Todd R, additional, Qi, Jun, additional, and Filbin, Mariella G, additional

Published
2023
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45. Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq

Author

Filbin, Mariella G., Tirosh, Itay, Hovestadt, Volker, Shaw, McKenzie L., Escalante, Leah E., Mathewson, Nathan D., Neftel, Cyril, Frank, Nelli, Pelton, Kristine, Hebert, Christine M., Haberler, Christine, Yizhak, Keren, Gojo, Johannes, Egervari, Kristof, Mount, Christopher, van Galen, Peter, Bonal, Dennis M., Nguyen, Quang-De, Beck, Alexander, Sinai, Claire, Czech, Thomas, Dorfer, Christian, Goumnerova, Liliana, Lavarino, Cinzia, Carcaboso, Angel M., Mora, Jaume, Mylvaganam, Ravindra, Luo, Christina C., Peyr, Andreas, Popović, Mara, Azizi, Amedeo, Batchelor, Tracy. T., Frosch, Matthew P., Martinez-Lage, Maria, Kieran, Mark W., Bandopadhayay, Pratiti, Beroukhim, Rameen, Fritsch, Gerhard, Getz, Gad, Rozenblatt-Rosen, Orit, Wucherpfennig, Kai W., Louis, David N., Monje, Michelle, Slavc, Irene, Ligon, Keith L., Golub, Todd R., Regev, Aviv, Bernstein, Bradley E., and Suvà, Mario L.

Published
2018

47. International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma

Author

Tsoli, Maria, Shen, Han, Mayoh, Chelsea, Franshaw, Laura, Ehteda, Anahid, Upton, Danielle, Carvalho, Diana, Vinci, Maria, Meel, Michael H., van Vuurden, Dannis, Plessier, Alexander, Castel, David, Drissi, Rachid, Farrell, Michael, Cryan, Jane, Crimmins, Darach, Caird, John, Pears, Jane, Francis, Stephanie, Ludlow, Louise E. A., Carai, Andrea, Mastronuzzi, Angela, Liu, Bing, Hansford, Jordan, Gottardo, Nick, Hassall, Tim, Kirby, Maria, Fouladi, Maryam, Hawkins, Cynthia, Monje, Michelle, Grill, Jacques, Jones, Chris, Hulleman, Esther, and Ziegler, David S.

Published
2019
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48. Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells

Author

Vinci, Mara, Burford, Anna, Molinari, Valeria, Kessler, Ketty, Popov, Sergey, Clarke, Matthew, Taylor, Kathryn R., Pemberton, Helen N., Lord, Christopher J., Gutteridge, Alice, Forshew, Tim, Carvalho, Diana, Marshall, Lynley V., Qin, Elizabeth Y., Ingram, Wendy J., Moore, Andrew S., Ng, Ho-Keung, Trabelsi, Saoussen, H’mida-Ben Brahim, Dorra, Entz-Werle, Natacha, Zacharoulis, Stergios, Vaidya, Sucheta, Mandeville, Henry C., Bridges, Leslie R., Martin, Andrew J., Al-Sarraj, Safa, Chandler, Christopher, Sunol, Mariona, Mora, Jaume, de Torres, Carmen, Cruz, Ofelia, Carcaboso, Angel M., Monje, Michelle, Mackay, Alan, and Jones, Chris

Published
2018
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50. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq

Author

Venteicher, Andrew S., Tirosh, Itay, Hebert, Christine, Yizhak, Keren, Neftel, Cyril, Filbin, Mariella G., Hovestadt, Volker, Escalante, Leah E., Shaw, McKenzie L., Rodman, Christopher, Gillespie, Shawn M., Dionne, Danielle, Luo, Christina C., Ravichandran, Hiranmayi, Mylvaganam, Ravindra, Mount, Christopher, Onozato, Maristela L., Nahed, Brian V., Wakimoto, Hiroaki, Curry, William T., Iafrate, A. John, Rivera, Miguel N., Frosch, Matthew P., Golub, Todd R., Brastianos, Priscilla K., Getz, Gad, Patel, Anoop P., Monje, Michelle, Cahill, Daniel P., Rozenblatt-Rosen, Orit, Louis, David N., Bernstein, Bradley E., Regev, Aviv, and Suvà, Mario L.

Published
2017

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