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1. Author Correction: Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Author

Kevin Bielamowicz, David Przelicki, Avesta Rastan, Alex Manno, Kaitlin Kharas, Nabil Ahmed, Joonas Haapasalo, Alyssa C. M. Joynt, Claudia M. Kuzan-Fischer, Randy Van Ommeren, Meenakshi Hegde, Craig Daniels, Mads Daugaard, Cory Richman, Poul H. Sorensen, Kenneth Aldape, Raul Suarez, Alberto Delaidelli, Polina Balin, A. Sorana Morrissy, Stephen Yip, Pasqualino De Antonellis, Lei Qin, Carolina Nor, Stephen C. Mack, Betty Luu, Ahmed Z. Gad, Cynthia Hawkins, Antony Michealraj, Sujith K. Joseph, Zied Abdullaev, Borja L. Holgado, Ning Huang, Ana Guerreiro Stucklin, Kristen Fousek, Xiaochong Wu, John M. Maris, Livia Garzia, Vijay Ramaswamy, Jonelle G. Pallota, Uri Tabori, Michelle Ly, Matthew L. Baker, Michael D. Taylor, Tajana Douglas, Dilakshan Srikanthan, Florence M.G. Cavalli, Juliette Hukin, Srinidhi Varadharajan, Martin Komosa, Sachin Kumar, Maria C. Vladoiu, Olga Sirbu, Claudia C. Faria, Laura K. Donovan, and Liam D. Hendrikse

Subjects
Medulloblastoma, Oncology, Ependymoma, medicine.medical_specialty, business.industry, medicine.medical_treatment, General Medicine, Immunotherapy, medicine.disease, CNS cancer, General Biochemistry, Genetics and Molecular Biology, Text mining, Cerebrospinal fluid, Cancer immunotherapy, Internal medicine, medicine, Car t cells, business
Published
2021

2. Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

Author

Samuel Weiss, Leo J.Y. Kim, Xiaochong Wu, Randy Van Ommeren, Yanqing Jiang, Kaitlin Kharas, Evgeny Kanshin, Moloud Ahmadi, Alberto Delaidelli, Geneviève Deblois, David Przelicki, Stephane Angers, Hiromichi Suzuki, Sameer Agnihotri, Bradly G. Wouters, Graham MacLeod, Ricky Tsai, Pasqualino De Antonellis, Michelle Ly, Stacey L. Krumholtz, Paul Guilhamon, James Loukides, Ravi N. Vellanki, Alex Rasnitsyn, Hamza Farooq, Daniel Schramek, Nada Jabado, María Sánchez-Osuna, Laura K. Donovan, Vijay Ramaswamy, Ibrahim El-Hamamy, Joonas Haapasalo, Jeremy N. Rich, Michael D. Taylor, Benjamin A. Garcia, Mike Tyers, Kyle Juraschka, Winnie Ong, Olivier Saulnier, Panagiotis Prinos, John J.Y. Lee, Borja L. Holgado, Olga Sirbu, Craig Daniels, Cheryl H. Arrowsmith, Cory Richman, Poul H. Sorensen, Kulandaimanuvel Antony Michealraj, Sheila K. Singh, Andrea Bajic, Polina Balin, Stephen C. Mack, Betty Luu, Fiona J. Coutinho, Dilakshan Srikanthan, Florence M.G. Cavalli, Sachin Kumar, Evan Y. Wang, Mathieu Lupien, Peter B. Dirks, Maria C. Vladoiu, Lincoln Stein, Livia Garzia, Ahmad Malik, John Wojcik, Avesta Rastan, Michealraj, K. A., Kumar, S. A., Kim, L. J. Y., Cavalli, F. M. G., Przelicki, D., Wojcik, J. B., Delaidelli, A., Bajic, A., Saulnier, O., Macleod, G., Vellanki, R. N., Vladoiu, M. C., Guilhamon, P., Ong, W., Lee, J. J. Y., Jiang, Y., Holgado, B. L., Rasnitsyn, A., Malik, A. A., Tsai, R., Richman, C. M., Juraschka, K., Haapasalo, J., Wang, E. Y., De Antonellis, P., Suzuki, H., Farooq, H., Balin, P., Kharas, K., Van Ommeren, R., Sirbu, O., Rastan, A., Krumholtz, S. L., Ly, M., Ahmadi, M., Deblois, G., Srikanthan, D., Luu, B., Loukides, J., Wu, X., Garzia, L., Ramaswamy, V., Kanshin, E., Sanchez-Osuna, M., El-Hamamy, I., Coutinho, F. J., Prinos, P., Singh, S., Donovan, L. K., Daniels, C., Schramek, D., Tyers, M., Weiss, S., Stein, L. D., Lupien, M., Wouters, B. G., Garcia, B. A., Arrowsmith, C. H., Sorensen, P. H., Angers, S., Jabado, N., Dirks, P. B., Mack, S. C., Agnihotri, S., Rich, J. N., and Taylor, M. D.

Subjects
Epigenomics, Ependymoma, Male, ependymoma, Epigenomic, Somatic cell, cancer metabolism, Infratentorial Neoplasms, Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, Histones, Brain Neoplasm, 03 medical and health sciences, Epigenome, 0302 clinical medicine, Histone demethylation, Histone methylation, medicine, Animals, Humans, Epigenetics, 030304 developmental biology, hindbrain development, Cell Proliferation, Infratentorial Neoplasm, 0303 health sciences, Brain Neoplasms, Animal, Lysine, Infant, DNA Methylation, medicine.disease, microenvironment, Mice, Inbred C57BL, Histone, Acetylation, paediatric cancer, Mutation, biology.protein, Cancer research, 030217 neurology & neurosurgery, epigenetic, Human
Abstract

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma. Hypoxia reprograms the cellular metabolome and epigenome to promote growth of the most lethal ependymomas.

Published
2020

3. Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Author

Carolina Nor, Martin Komosa, Olga Sirbu, Nabil Ahmed, Joonas Haapasalo, Kristen Fousek, Jonelle G. Pallota, Betty Luu, Cynthia Hawkins, Kenneth Aldape, Uri Tabori, David Przelicki, Srinidhi Varadharajan, Liam D. Hendrikse, Meenakshi Hegde, Claudia M. Kuzan-Fischer, Ana Guerreiro Stucklin, Tajana Douglas, Ahmed Z. Gad, Xiaochong Wu, Randy Van Ommeren, Polina Balin, Alex Manno, Sachin Kumar, Raul Suarez, Avesta Rastan, Craig Daniels, Mads Daugaard, Maria C. Vladoiu, Stephen Yip, Cory Richman, Michelle Ly, Matthew L. Baker, Kaitlin Kharas, Laura K. Donovan, Stephen C. Mack, Claudia C. Faria, Pasqualino De Antonellis, Ning Huang, Poul H. Sorensen, Zied Abdullaev, Lei Qin, Livia Garzia, Alyssa C. M. Joynt, A. Sorana Morrissy, Michael D. Taylor, Sujith K. Joseph, Antony Michealraj, Dilakshan Srikanthan, Florence M.G. Cavalli, Borja L. Holgado, John M. Maris, Alberto Delaidelli, Vijay Ramaswamy, Kevin Bielamowicz, Juliette Hukin, Donovan, L. K., Delaidelli, A., Joseph, S. K., Bielamowicz, K., Fousek, K., Holgado, B. L., Manno, A., Srikanthan, D., Gad, A. Z., Van Ommeren, R., Przelicki, D., Richman, C., Ramaswamy, V., Daniels, C., Pallota, J. G., Douglas, T., Joynt, A. C. M., Haapasalo, J., Nor, C., Vladoiu, M. C., Kuzan-Fischer, C. M., Garzia, L., Mack, S. C., Varadharajan, S., Baker, M. L., Hendrikse, L., Ly, M., Kharas, K., Balin, P., Wu, X., Qin, L., Huang, N., Stucklin, A. G., Morrissy, A. S., Cavalli, F. M. G., Luu, B., Suarez, R., De Antonellis, P., Michealraj, A., Rastan, A., Hegde, M., Komosa, M., Sirbu, O., Kumar, S. A., Abdullaev, Z., Faria, C. C., Yip, S., Hukin, J., Tabori, U., Hawkins, C., Aldape, K., Daugaard, M., Maris, J. M., Sorensen, P. H., Ahmed, N., and Taylor, M. D.

Subjects
0301 basic medicine, Ependymoma, Male, medicine.medical_treatment, T-Lymphocytes, Immunotherapy, Adoptive, Mice, 0302 clinical medicine, Cerebrospinal fluid, Drug Delivery Systems, HEK293 Cell, Cancer immunotherapy, Tumor Cells, Cultured, Neoplasm Metastasis, Child, Cerebrospinal Fluid, Receptors, Chimeric Antigen, Brain Neoplasms, General Medicine, Neoplasm Metastasi, Treatment Outcome, 030220 oncology & carcinogenesis, Child, Preschool, Female, Cancer Vaccine, Human, Cancer Vaccines, General Biochemistry, Genetics and Molecular Biology, Brain Neoplasm, 03 medical and health sciences, medicine, Animals, Humans, Cerebellar Neoplasms, neoplasms, Injections, Intraventricular, Medulloblastoma, Animal, business.industry, Cerebellar Neoplasm, Infant, Immunotherapy, Recurrent Medulloblastoma, medicine.disease, Interleukin-13 receptor, Xenograft Model Antitumor Assays, Chimeric antigen receptor, 030104 developmental biology, HEK293 Cells, T-Lymphocyte, Cancer research, business, Drug Delivery System
Abstract

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood–brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.

Published
2019

4. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

Author

Anne Jouvet, Ana Gutiérrez-Fernández, Namal Abeysundara, Olivier Ayrault, Vijay Ramaswamy, Charles G. Eberhart, Jennifer A. Chan, Johan M. Kros, Xiaochong Wu, Sachin Kumar, Seung-Ki Kim, Maria C. Vladoiu, Noriyuki Kijima, Xose S. Puente, Ian F. Pollack, Robert J. Wechsler-Reya, Boleslaw Lach, Almos Klekner, Ander Diaz-Navarro, Claudia C. Faria, Lincoln Stein, Nicole Gauer, Enrique López-Aguilar, Nada Jabado, Amulya A. Nageswara Rao, Livia Garzia, David Malkin, Stefan M. Pfister, Jiannis Ragoussis, Maura Massimino, James M. Olson, Caterina Giannini, Hamza Farooq, Pim J. French, Florence M.G. Cavalli, Anna Goldenberg, John A. Calarco, Joshua B. Rubin, Maria Luisa Garrè, Betty Luu, László Bognár, Weifan Dong, Shimin Shuai, Antoine Forget, Jun Wang, Ichiyo Shibahara, Pasqualino De Antonellis, William A. Weiss, Marco A. Marra, Lola B. Chambless, Patryk Skowron, Wiesława Grajkowska, Jiao Zhang, Ali Momin, Erwin G. Van Meir, Michelle Fèvre-Montange, Rajeev Vibhakar, Ho Keung Ng, David Przelicki, Hiromichi Suzuki, Kyle Juraschka, Craig Daniels, A. Sorana Morrissy, Toshihiro Kumabe, Xi Huang, Wai Sang Poon, Swneke D. Bailey, Michael D. Taylor, Pathology, Neurology, Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France. 4Université Paris Sud, Université Paris- Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France., Institut Curie [Paris], Suzuki H., Kumar S.A., Shuai S., Diaz-Navarro A., Gutierrez-Fernandez A., De Antonellis P., Cavalli F.M.G., Juraschka K., Farooq H., Shibahara I., Vladoiu M.C., Zhang J., Abeysundara N., Przelicki D., Skowron P., Gauer N., Luu B., Daniels C., Wu X., Forget A., Momin A., Wang J., Dong W., Kim S.-K., Grajkowska W.A., Jouvet A., Fevre-Montange M., Garre M.L., Nageswara Rao A.A., Giannini C., Kros J.M., French P.J., Jabado N., Ng H.-K., Poon W.S., Eberhart C.G., Pollack I.F., Olson J.M., Weiss W.A., Kumabe T., Lopez-Aguilar E., Lach B., Massimino M., Van Meir E.G., Rubin J.B., Vibhakar R., Chambless L.B., Kijima N., Klekner A., Bognar L., Chan J.A., Faria C.C., Ragoussis J., Pfister S.M., Goldenberg A., Wechsler-Reya R.J., Bailey S.D., Garzia L., Morrissy A.S., Marra M.A., Huang X., Malkin D., Ayrault O., Ramaswamy V., Puente X.S., Calarco J.A., Stein L., Taylor M.D., Repositório da Universidade de Lisboa, Suzuki, H., Kumar, S. A., Shuai, S., Diaz-Navarro, A., Gutierrez-Fernandez, A., De Antonellis, P., Cavalli, F. M. G., Juraschka, K., Farooq, H., Shibahara, I., Vladoiu, M. C., Zhang, J., Abeysundara, N., Przelicki, D., Skowron, P., Gauer, N., Luu, B., Daniels, C., Wu, X., Forget, A., Momin, A., Wang, J., Dong, W., Kim, S. -K., Grajkowska, W. A., Jouvet, A., Fevre-Montange, M., Garre, M. L., Nageswara Rao, A. A., Giannini, C., Kros, J. M., French, P. J., Jabado, N., Ng, H. -K., Poon, W. S., Eberhart, C. G., Pollack, I. F., Olson, J. M., Weiss, W. A., Kumabe, T., Lopez-Aguilar, E., Lach, B., Massimino, M., Van Meir, E. G., Rubin, J. B., Vibhakar, R., Chambless, L. B., Kijima, N., Klekner, A., Bognar, L., Chan, J. A., Faria, C. C., Ragoussis, J., Pfister, S. M., Goldenberg, A., Wechsler-Reya, R. J., Bailey, S. D., Garzia, L., Morrissy, A. S., Marra, M. A., Huang, X., Malkin, D., Ayrault, O., Ramaswamy, V., Puente, X. S., Calarco, J. A., Stein, L., Taylor, M. D., and Olivier, AYRAULT

Subjects
0301 basic medicine, Adult, Adolescent, RNA Splicing, [SDV]Life Sciences [q-bio], Biology, Article, 03 medical and health sciences, 0302 clinical medicine, GLI2, RNA, Small Nuclear, medicine, Humans, G%29+of+U1+spliceosomal+small+nuclear+RNAs+%28snRNAs%29%22">subgroups of medulloblastoma, recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs), Hedgehog Proteins, Sonic hedgehog, Cerebellar Neoplasms, Gene, ComputingMilieux_MISCELLANEOUS, Medulloblastoma, Multidisciplinary, Cerebellar Neoplasm, Alternative splicing, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Alternative Splicing, 030104 developmental biology, PTCH1, RNA Splice Site, 030220 oncology & carcinogenesis, RNA splicing, Mutation, Cancer research, biology.protein, RNA Splice Sites, Hedgehog Protein, Small nuclear RNA, Human
Abstract

© The Author(s), under exclusive licence to Springer Nature Limited 2019, In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only

Published
2019

5. Childhood cerebellar tumours mirror conserved fetal transcriptional programs

Author

Karen Ng, Vijay Ramaswamy, Ibrahim El-Hamamy, Jennifer A. Chan, Trevor J. Pugh, Xiaochong Wu, Vernon Fong, Stephen C. Mack, Sachin Kumar, Maria C. Vladoiu, Laura K. Donovan, Lincoln Stein, Alexandra L. Joyner, Nada Jabado, Livia Garzia, David Malkin, Eric M. Thompson, Antony Michealraj, John J.Y. Lee, Hamza Farooq, Lawrence E. Heisler, Faiyaz Notta, Peter B. Dirks, Liam D. Hendrikse, Sheila K. Singh, Borja L. Holgado, Florence M.G. Cavalli, Betty Luu, Yogi Sundaravadanam, Marco A. Marra, Patryk Skowron, Maleeha Qazi, David Przelicki, Hiromichi Suzuki, Kyle Juraschka, Craig Daniels, A. Sorana Morrissy, Michael D. Taylor, and Claudia L. Kleinman

Subjects
0301 basic medicine, Time Factors, Transcription, Genetic, Population, Biology, Article, Evolution, Molecular, 03 medical and health sciences, Mice, 0302 clinical medicine, Fetus, Cerebellum, medicine, Animals, Humans, Progenitor cell, Sonic hedgehog, education, Cerebellar Neoplasms, Child, Medulloblastoma, education.field_of_study, Multidisciplinary, Cerebellar Pilocytic Astrocytoma, Sequence Analysis, RNA, Gene Expression Regulation, Developmental, Glioma, Nestin, Granule cell, medicine.disease, Gene Expression Regulation, Neoplastic, Editorial Commentary, 030104 developmental biology, medicine.anatomical_structure, nervous system, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, Stem cell, Single-Cell Analysis, Transcriptome
Abstract

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood. Sequencing data from the developing cerebellum are compared with bulk sequencing data from paediatric tumours, providing insights into their potential origins and suggesting that many cerebellar tumours have their origins early in utero.

Published
2018

6. Childhood Cerebellar Tumors Mirror Conserved Fetal Transcriptional Programs

Author

Antony MichaelRaj, David Malkin, Florence Cavalli, Marco A. Marra, Patryk Skowron, Craig Daniels, Maleeha Qazi, Sachin Kumar, Hiromichi Suzuki, Vijay Ramaswamy, Ibrahim El-Hamamy, Maria C. Vladoiu, Livia Garzia, Jennifer A. Chan, Trevor J. Pugh, Faiyaz Notta, Sheila K. Singh, Lincoln Stein, Hamza Farooq, Betty Luu, David Przelicki, Kyle Juraschka, Laura K. Donovan, Sorana Morrissy, Stephen C. Mack, Peter B. Dirks, Nada Jabado, Alexandra L. Joyner, Borja L Holgado, Xiaochong Wu, John J.Y. Lee, Michael D. Taylor, and Claudia L. Kleinman

Subjects
Medulloblastoma, Cerebellum, education.field_of_study, Cerebellar Pilocytic Astrocytoma, Population, Biology, Nestin, medicine.disease, Granule cell, medicine.anatomical_structure, nervous system, medicine, Cancer research, biology.protein, Stem cell, Sonic hedgehog, education
Abstract

SummaryThe study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. We used single-cell transcriptomics to study >60,000 cells from the developing murine cerebellum, and show that different molecular subgroups of childhood cerebellar tumors mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. Sonic Hedgehog medulloblastoma transcriptionally mirrors the granule cell hierarchy as expected, whereas Group 3 medulloblastoma resemble Nestin+ve stem cells, Group 4 medulloblastomas resemble unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumors demonstrates that many bulk tumors contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumors as a disorder of early brain development, and provide a proximate explanation for the peak incidence of cerebellar tumors in early childhood.

Published
2018
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