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1. Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author

Hendrikse, Liam D, Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H, Erickson, Anders W, Ong, Winnie, Gordon, Victor, Coudière-Morrison, Ludivine, Mercier, Audrey L, Shokouhian, Mohammad, Suárez, Raúl A, Ly, Michelle, Borlase, Stephanie, Scott, David S, Vladoiu, Maria C, Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y, Kumar, Sachin A, Balin, Polina, Visvanathan, Abhirami, Lee, John JY, Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L, Luu, Betty, Bérubé, Pierre, Wang, Yu C, Pfister, Stefan M, Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, François, Masliah-Planchon, Julien, Grajkowska, Wieslawa A, Loukides, James, Dirks, Peter, Fèvre-Montange, Michelle, Jouvet, Anne, French, Pim J, Kros, Johan M, Zitterbart, Karel, Bailey, Swneke D, Eberhart, Charles G, Rao, Amulya AN, Giannini, Caterina, Olson, James M, Garami, Miklós, Hauser, Peter, Phillips, Joanna J, Ra, Young S, de Torres, Carmen, Mora, Jaume, Li, Kay KW, Ng, Ho-Keung, Poon, Wai S, Pollack, Ian F, López-Aguilar, Enrique, Gillespie, G Yancey, Van Meter, Timothy E, Shofuda, Tomoko, Vibhakar, Rajeev, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Kumabe, Toshihiro, Jung, Shin, Lach, Boleslaw, Iolascon, Achille, Ferrucci, Veronica, de Antonellis, Pasqualino, Zollo, Massimo, Cinalli, Giuseppe, Robinson, Shenandoah, Stearns, Duncan S, Van Meir, Erwin G, Porrati, Paola, Finocchiaro, Gaetano, Massimino, Maura, Carlotti, Carlos G, Faria, Claudia C, Roussel, Martine F, Boop, Frederick, Chan, Jennifer A, Aldinger, Kimberly A, Razavi, Ferechte, Silvestri, Evelina, McLendon, Roger E, and Thompson, Eric M

Subjects
General Science & Technology, 1.1 Normal biological development and functioning, Muscle Proteins, Metencephalon, Rare Diseases, Underpinning research, Cerebellum, Humans, 2.1 Biological and endogenous factors, Cell Lineage, Hedgehog Proteins, Aetiology, Cerebellar Neoplasms, Histone Demethylases, Otx Transcription Factors, Neurosciences, Core Binding Factor alpha Subunits, Cell Differentiation, Stem Cell Research, Brain Disorders, Repressor Proteins, Ki-67 Antigen, Mutation, Stem Cell Research - Nonembryonic - Non-Human, T-Box Domain Proteins, Medulloblastoma, Transcription Factors
Abstract

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Published
2022

2. A brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours

Author

Hamed, Akram A, Kunz, Daniel J, El-Hamamy, Ibrahim, Trinh, Quang M, Subedar, Omar D, Richards, Laura M, Foltz, Warren, Bullivant, Garrett, Ware, Matthaeus, Vladoiu, Maria C, Zhang, Jiao, Raj, Antony M, Pugh, Trevor J, Taylor, Michael D, Teichmann, Sarah A, Stein, Lincoln D, Simons, Benjamin D, Dirks, Peter B, Hamed, Akram A [0000-0001-9239-2942], Kunz, Daniel J [0000-0003-3597-6591], El-Hamamy, Ibrahim [0000-0003-3800-419X], Trinh, Quang M [0000-0002-3602-2290], Richards, Laura M [0000-0003-3414-7628], Vladoiu, Maria C [0000-0001-8644-0581], Taylor, Michael D [0000-0001-7009-3466], Teichmann, Sarah A [0000-0002-6294-6366], Simons, Benjamin D [0000-0002-3875-7071], Dirks, Peter B [0000-0001-5718-6465], Apollo - University of Cambridge Repository, Kunz, Daniel [0000-0003-3597-6591], Teichmann, Sarah [0000-0002-6294-6366], and Simons, Benjamin [0000-0002-3875-7071]

Subjects
64, Telencephalon, Multidisciplinary, Neurogenesis, 631/136/532/2182, article, General Physics and Astronomy, Brain, General Chemistry, Glioma, 13, General Biochemistry, Genetics and Molecular Biology, 49, Mice, 13/100, 692/699/67/1922, Animals, Humans, 64/60, Child, 631/67/71, Cerebrum, 49/91
Abstract

Funder: Canadian Institute of Health Research (155960), Human cerebral cancers are known to contain cell types resembling the varying stages of neural development. However, the basis of this association remains unclear. Here, we map the development of mouse cerebrum across the developmental time-course, from embryonic day 12.5 to postnatal day 365, performing single-cell transcriptomics on >100,000 cells. By comparing this reference atlas to single-cell data from >100 glial tumours of the adult and paediatric human cerebrum, we find that tumour cells have an expression signature that overlaps with temporally restricted, embryonic radial glial precursors (RGPs) and their immediate sublineages. Further, we demonstrate that prenatal transformation of RGPs in a genetic mouse model gives rise to adult cerebral tumours that show an embryonic/juvenile RGP identity. Together, these findings implicate the acquisition of embryonic-like states in the genesis of adult glioma, providing insight into the origins of human glioma, and identifying specific developmental cell types for therapeutic targeting.

Published
2021

3. Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis

Author

Huang, Miller, Tailor, Jignesh, Zhen, Qiqi, Gillmor, Aaron H, Miller, Matthew L, Weishaupt, Holger, Chen, Justin, Zheng, Tina, Nash, Emily K, McHenry, Lauren K, An, Zhenyi, Ye, Fubaiyang, Takashima, Yasuhiro, Clarke, James, Ayetey, Harold, Cavalli, Florence MG, Luu, Betty, Moriarity, Branden S, Ilkhanizadeh, Shirin, Chavez, Lukas, Yu, Chunying, Kurian, Kathreena M, Magnaldo, Thierry, Sevenet, Nicolas, Koch, Philipp, Pollard, Steven M, Dirks, Peter, Snyder, Michael P, Largaespada, David A, Cho, Yoon Jae, Phillips, Joanna J, Swartling, Fredrik J, Morrissy, A Sorana, Kool, Marcel, Pfister, Stefan M, Taylor, Michael D, Smith, Austin, Weiss, William A, Clarke, James [0000-0002-5932-032X], Smith, Austin [0000-0002-3029-4682], and Apollo - University of Cambridge Repository

Subjects
Carcinogenesis, Cell- och molekylärbiologi, Neuroepithelial Cells, Mice, SCID, Regenerative Medicine, Medical and Health Sciences, SHH, DEAD-box RNA Helicases, Mice, Neural Stem Cells, Stem Cell Research - Nonembryonic - Human, human pluripotent stem cells, Cancer, Pediatric, Heterologous, N-Myc Proto-Oncogene Protein, Brain Neoplasms, Basal Cell Nevus Syndrome, Biological Sciences, Neoplasm Proteins, Patched-1 Receptor, neuroepithelial stem cells, Stem Cell Research - Nonembryonic - Non-Human, Development of treatments and therapeutic interventions, Genetic Engineering, Biotechnology, Pluripotent Stem Cells, Cellbiologi, Pediatric Cancer, Transplantation, Heterologous, SCID, medulloblastoma, Article, Rare Diseases, Genetics, Animals, Humans, Genetic Predisposition to Disease, neoplasms, Transplantation, 5.2 Cellular and gene therapies, Animal, Neurosciences, Cell Biology, Stem Cell Research, Brain Disorders, Brain Cancer, stomatognathic diseases, Disease Models, Animal, Disease Models, Cell and Molecular Biology, Developmental Biology, Stem Cell Transplantation
Abstract

SUMMARY Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma., Graphical Abstract, In Brief Huang, Tailor, et al. show that neuroepithelial stem (NES) cells derived from normal induced pluripotent stem cells (iPSCs) provide a renewable humancell-based resource to evaluate genetic mutations in medulloblastoma. Misexpression of MYCN in both otherwise-normal NES cells and PTCH1+/− NES cells derived from patients with Gorlin syndrome each generated medulloblastoma in mice.

Published
2019

5. Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Author

Northcott, Paul A, Shih, David JH, Peacock, John, Garzia, Livia, Morrissy, A Sorana, Zichner, Thomas, Stütz, Adrian M, Korshunov, Andrey, Reimand, Jüri, Schumacher, Steven E, Beroukhim, Rameen, Ellison, David W, Marshall, Christian R, Lionel, Anath C, Mack, Stephen, Dubuc, Adrian, Yao, Yuan, Ramaswamy, Vijay, Luu, Betty, Rolider, Adi, Cavalli, Florence MG, Wang, Xin, Remke, Marc, Wu, Xiaochong, Chiu, Readman YB, Chu, Andy, Chuah, Eric, Corbett, Richard D, Hoad, Gemma R, Jackman, Shaun D, Li, Yisu, Lo, Allan, Mungall, Karen L, Nip, Ka Ming, Qian, Jenny Q, Raymond, Anthony GJ, Thiessen, Nina T, Varhol, Richard J, Birol, Inanc, Moore, Richard A, Mungall, Andrew J, Holt, Robert, Kawauchi, Daisuke, Roussel, Martine F, Kool, Marcel, Jones, David TW, Witt, Hendrick, Fernandez-L, Africa, Kenney, Anna M, Wechsler-Reya, Robert J, Dirks, Peter, Aviv, Tzvi, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Haberler, Christine C, Delattre, Olivier, Reynaud, Stéphanie S, Doz, François F, Pernet-Fattet, Sarah S, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Scheurlen, Wolfram, Eberhart, Charles G, Fèvre-Montange, Michelle, Jouvet, Anne, Pollack, Ian F, Fan, Xing, Muraszko, Karin M, Gillespie, G Yancey, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Kloosterhof, Nanne K, French, Pim J, Kros, Johan M, Olson, James M, Ellenbogen, Richard G, Zitterbart, Karel, Kren, Leos, Thompson, Reid C, Cooper, Michael K, Lach, Boleslaw, McLendon, Roger E, Bigner, Darell D, Fontebasso, Adam, Albrecht, Steffen, Jabado, Nada, Lindsey, Janet C, Bailey, Simon, Gupta, Nalin, Weiss, William A, Bognár, László, Klekner, Almos, Van Meter, Timothy E, Kumabe, Toshihiro, Tominaga, Teiji, Elbabaa, Samer K, Leonard, Jeffrey R, and Rubin, Joshua B

Subjects
Pediatric Research Initiative, DNA Copy Number Variations, Pediatric Cancer, General Science & Technology, Translocation, Nerve Tissue Proteins, Rare Diseases, Genetic, Transforming Growth Factor beta, Gene Duplication, Genetics, Humans, Hedgehog Proteins, Cerebellar Neoplasms, Fusion, Child, Cancer, Oncogene Proteins, Pediatric, Genome, NF-kappa B, Neurosciences, Proteins, Genomics, myc, Brain Disorders, Brain Cancer, Genes, 5.1 Pharmaceuticals, Genomic Structural Variation, RNA, Long Noncoding, Development of treatments and therapeutic interventions, Carrier Proteins, Medulloblastoma, Signal Transduction, Human
Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Published
2012

8. OUTCOME OF BRAF V600E PEDIATRIC GLIOMAS TREATED WITH TARGETED BRAF INHIBITION

Author

Nobre, Liana, Zapotocky, Michal, Ramaswamy, Vijay, Ryall, Scott, Bennet, Julie, Alderete, Daniel, Balaguer Guill, Julia, Baroni, Lorena, Bartels, Ute, Bavle, Abhishek, Bornhorst, Miriam, Boue, Daniel R., Canete, Adela, Chintagumpala, Murali, Coven, Scott L., Cruz, Ofelia, Dahiya, Sonika, Dirks, Peter, Dunkel, Ira J., Eisenstat, David, Conter, Cecile Faure, Finch, Elizabeth, Finlay, Jonathan L., Frappaz, Didier, Garre, Maria Luisa, Gauvain, Karen, Bechensteen, Anne Grete, Hansford, Jordan R., Harting, Inga, Hauser, Peter, Hazrati, Lili-Naz, Huang, Annie, Injac, Sarah G., Iurilli, Valentina, Karajannis, Matthias, Kaur, Gurcharanjeet, Kyncl, Martin, Krskova, Lenka, Laperriere, Normad, Larouche, Valerie, Lassaletta, Alvaro, Leary, Sarah, Lin, Frank, Mascelli, Samantha, Mckeown, Tara, Till Milde, Morales La Madrid, Andres, Morana, Giovanni, Morse, Helena, Mushtaq, Naureen, Osorio, Diana S., Packer, Roger, Pavelka, Zdenek, Quiroga-Cantero, Eduardo, Rutka, James, Sabel, Magnus, Salgado, Duarte, Solano, Palma, Sterba, Jaroslav, Su, Jack, Sumerauer, David, Taylor, Michael D., Toledano, Helen, Tsang, Derek S., Fernandes, Mariana Valente, Landeghem, Frank, Tilburg, Cornelis M., Wilson, Bev, Witt, Olaf, Zamecbik, Josef, Bouffet, Eric, Hawkins, Cynthia, and Tabori, Uri

9. Intratumoral Genetic and Functional Heterogeneity in Pediatric Glioblastoma

Author

Hoffman, Mary, Gillmor, Aaron H, Kunz, Daniel J, Johnston, Michael J, Nikolic, Ana, Narta, Kiran, Zarrei, Mehdi, King, Jennifer, Ellestad, Katrina, Dang, Ngoc Ha, Cavalli, Florence MG, Kushida, Michelle M, Coutinho, Fiona J, Zhu, Yuankun, Luu, Betty, Ma, Yussanne, Mungall, Andrew J, Moore, Richard, Marra, Marco A, Taylor, Michael D, Pugh, Trevor J, Dirks, Peter B, Strother, Douglas, Lafay-Cousin, Lucie, Resnick, Adam C, Scherer, Stephen, Senger, Donna L, Simons, Benjamin D, Chan, Jennifer A, Morrissy, A Sorana, and Gallo, Marco

Subjects
Whole Genome Sequencing, Brain Neoplasms, Gene Expression Profiling, Xenograft Model Antitumor Assays, 3. Good health, Mice, Mutation, Biomarkers, Tumor, Neoplastic Stem Cells, Tumor Cells, Cultured, Animals, Humans, Longitudinal Studies, Neoplasm Recurrence, Local, Child, Glioblastoma
Abstract

Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand the mechanisms of tumor evolution in this cancer, we performed whole-genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of nonsynonymous single-nucleotide variants being shared in diagnostic-recurrent pairs. To track the origins of the mutational events observed in pGBM, we generated whole-genome datasets for two patients and their parents. These trios showed that genetic variants could be (i) somatic, (ii) inherited from a healthy parent, or (iii) de novo in the germlines of pGBM patients. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to nondividing cells. Interestingly, radiation and antimitotic chemotherapeutics did not increase overall tumor burden upon recurrence. These findings support an important role for slow-cycling stem cell populations in contributing to recurrences, because slow-cycling cell populations are expected to be less prone to genotoxic stress induced by these treatments and therefore would accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM. SIGNIFICANCE: This work challenges several assumptions regarding the genetic organization of pediatric GBM and highlights mutagenic programs that start during early prenatal development.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/9/2111/F1.large.jpg.

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