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1. Developmental basis of SHH medulloblastoma heterogeneity

Author

Maxwell P. Gold, Winnie Ong, Andrew M. Masteller, David R. Ghasemi, Julie Anne Galindo, Noel R. Park, Nhan C. Huynh, Aneesh Donde, Veronika Pister, Raul A. Saurez, Maria C. Vladoiu, Grace H. Hwang, Tanja Eisemann, Laura K. Donovan, Adam D. Walker, Joseph Benetatos, Christelle Dufour, Livia Garzia, Rosalind A. Segal, Robert J. Wechsler-Reya, Jill P. Mesirov, Andrey Korshunov, Kristian W. Pajtler, Scott L. Pomeroy, Olivier Ayrault, Shawn M. Davidson, Jennifer A. Cotter, Michael D. Taylor, and Ernest Fraenkel

Subjects
Science
Abstract

Abstract Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies.

Published
2024
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2. DeepVelo: deep learning extends RNA velocity to multi-lineage systems with cell-specific kinetics

Author

Haotian Cui, Hassaan Maan, Maria C. Vladoiu, Jiao Zhang, Michael D. Taylor, and Bo Wang

Subjects
RNA velocity, Single-cell RNA sequencing, Deep Learning, Development, Cancer, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Existing RNA velocity estimation methods strongly rely on predefined dynamics and cell-agnostic constant transcriptional kinetic rates, assumptions often violated in complex and heterogeneous single-cell RNA sequencing (scRNA-seq) data. Using a graph convolution network, DeepVelo overcomes these limitations by generalizing RNA velocity to cell populations containing time-dependent kinetics and multiple lineages. DeepVelo infers time-varying cellular rates of transcription, splicing, and degradation, recovers each cell’s stage in the differentiation process, and detects functionally relevant driver genes regulating these processes. Application to various developmental and pathogenic processes demonstrates DeepVelo’s capacity to study complex differentiation and lineage decision events in heterogeneous scRNA-seq data.

Published
2024
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3. A brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours

Author

Akram A. Hamed, Daniel J. Kunz, Ibrahim El-Hamamy, Quang M. Trinh, Omar D. Subedar, Laura M. Richards, Warren Foltz, Garrett Bullivant, Matthaeus Ware, Maria C. Vladoiu, Jiao Zhang, Antony M. Raj, Trevor J. Pugh, Michael D. Taylor, Sarah A. Teichmann, Lincoln D. Stein, Benjamin D. Simons, and Peter B. Dirks

Subjects
Science
Abstract

The link between neural development and tumourigenesis in adult glioma remains unclear. Here, the authors monitor the developmental stages of Sox2 + /− stem cells from a mouse model using single-cell RNA sequencing and suggest the acquisition of embryonic-like states in the adult glioma development.

Published
2022
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4. The transcriptional landscape of Shh medulloblastoma

Author

Patryk Skowron, Hamza Farooq, Florence M. G. Cavalli, A. Sorana Morrissy, Michelle Ly, Liam D. Hendrikse, Evan Y. Wang, Haig Djambazian, Helen Zhu, Karen L. Mungall, Quang M. Trinh, Tina Zheng, Shizhong Dai, Ana S. Guerreiro Stucklin, Maria C. Vladoiu, Vernon Fong, Borja L. Holgado, Carolina Nor, Xiaochong Wu, Diala Abd-Rabbo, Pierre Bérubé, Yu Chang Wang, Betty Luu, Raul A. Suarez, Avesta Rastan, Aaron H. Gillmor, John J. Y. Lee, Xiao Yun Zhang, Craig Daniels, Peter Dirks, David Malkin, Eric Bouffet, Uri Tabori, James Loukides, François P. Doz, Franck Bourdeaut, Olivier O. Delattre, Julien Masliah-Planchon, Olivier Ayrault, Seung-Ki Kim, David Meyronet, Wieslawa A. Grajkowska, Carlos G. Carlotti, Carmen de Torres, Jaume Mora, Charles G. Eberhart, Erwin G. Van Meir, Toshihiro Kumabe, Pim J. French, Johan M. Kros, Nada Jabado, Boleslaw Lach, Ian F. Pollack, Ronald L. Hamilton, Amulya A. Nageswara Rao, Caterina Giannini, James M. Olson, László Bognár, Almos Klekner, Karel Zitterbart, Joanna J. Phillips, Reid C. Thompson, Michael K. Cooper, Joshua B. Rubin, Linda M. Liau, Miklós Garami, Peter Hauser, Kay Ka Wai Li, Ho-Keung Ng, Wai Sang Poon, G. Yancey Gillespie, Jennifer A. Chan, Shin Jung, Roger E. McLendon, Eric M. Thompson, David Zagzag, Rajeev Vibhakar, Young Shin Ra, Maria Luisa Garre, Ulrich Schüller, Tomoko Shofuda, Claudia C. Faria, Enrique López-Aguilar, Gelareh Zadeh, Chi-Chung Hui, Vijay Ramaswamy, Swneke D. Bailey, Steven J. Jones, Andrew J. Mungall, Richard A. Moore, John A. Calarco, Lincoln D. Stein, Gary D. Bader, Jüri Reimand, Jiannis Ragoussis, William A. Weiss, Marco A. Marra, Hiromichi Suzuki, and Michael D. Taylor

Subjects
Science
Abstract

Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

Published
2021
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5. An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate

Author

Jamie Zagozewski, Ghazaleh M. Shahriary, Ludivine Coudière Morrison, Olivier Saulnier, Margaret Stromecki, Agnes Fresnoza, Gareth Palidwor, Christopher J. Porter, Antoine Forget, Olivier Ayrault, Cynthia Hawkins, Jennifer A. Chan, Maria C. Vladoiu, Lakshmikirupa Sundaresan, Janilyn Arsenio, Michael D. Taylor, Vijay Ramaswamy, and Tamra E. Werbowetski-Ogilvie

Subjects
Science
Abstract

OTX2 promotes tumour growth in Group 3 medulloblastoma. Here, the authors show that OTX2 regulates PAX3 to induce neural de-differentiation and promote tumourigenesis in Group 3 medulloblastoma.

Published
2020
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6. Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author

Liam D. Hendrikse, Parthiv Haldipur, Olivier Saulnier, Jake Millman, Alexandria H. Sjoboen, Anders W. Erickson, Winnie Ong, Victor Gordon, Ludivine Coudière-Morrison, Audrey L. Mercier, Mohammad Shokouhian, Raúl A. Suárez, Michelle Ly, Stephanie Borlase, David S. Scott, Maria C. Vladoiu, Hamza Farooq, Olga Sirbu, Takuma Nakashima, Shohei Nambu, Yusuke Funakoshi, Alec Bahcheli, J. Javier Diaz-Mejia, Joseph Golser, Kathleen Bach, Tram Phuong-Bao, Patryk Skowron, Evan Y. Wang, Sachin A. Kumar, Polina Balin, Abhirami Visvanathan, John J. Y. Lee, Ramy Ayoub, Xin Chen, Xiaodi Chen, Karen L. Mungall, Betty Luu, Pierre Bérubé, Yu C. Wang, Stefan M. Pfister, Seung-Ki Kim, Olivier Delattre, Franck Bourdeaut, François Doz, Julien Masliah-Planchon, Wieslawa A. Grajkowska, James Loukides, Peter Dirks, Michelle Fèvre-Montange, Anne Jouvet, Pim J. French, Johan M. Kros, Karel Zitterbart, Swneke D. Bailey, Charles G. Eberhart, Amulya A. N. Rao, Caterina Giannini, James M. Olson, Miklós Garami, Peter Hauser, Joanna J. Phillips, Young S. Ra, Carmen de Torres, Jaume Mora, Kay K. W. Li, Ho-Keung Ng, Wai S. Poon, Ian F. Pollack, Enrique López-Aguilar, G. Yancey Gillespie, Timothy E. Van Meter, Tomoko Shofuda, Rajeev Vibhakar, Reid C. Thompson, Michael K. Cooper, Joshua B. Rubin, Toshihiro Kumabe, Shin Jung, Boleslaw Lach, Achille Iolascon, Veronica Ferrucci, Pasqualino de Antonellis, Massimo Zollo, Giuseppe Cinalli, Shenandoah Robinson, Duncan S. Stearns, Erwin G. Van Meir, Paola Porrati, Gaetano Finocchiaro, Maura Massimino, Carlos G. Carlotti, Claudia C. Faria, Martine F. Roussel, Frederick Boop, Jennifer A. Chan, Kimberly A. Aldinger, Ferechte Razavi, Evelina Silvestri, Roger E. McLendon, Eric M. Thompson, Marc Ansari, Maria L. Garre, Fernando Chico, Pilar Eguía, Mario Pérezpeña, A. Sorana Morrissy, Florence M. G. Cavalli, Xiaochong Wu, Craig Daniels, Jeremy N. Rich, Steven J. M. Jones, Richard A. Moore, Marco A. Marra, Xi Huang, Jüri Reimand, Poul H. Sorensen, Robert J. Wechsler-Reya, William A. Weiss, Trevor J. Pugh, Livia Garzia, Claudia L. Kleinman, Lincoln D. Stein, Nada Jabado, David Malkin, Olivier Ayrault, Jeffrey A. Golden, David W. Ellison, Brad Doble, Vijay Ramaswamy, Tamra E. Werbowetski-Ogilvie, Hiromichi Suzuki, Kathleen J. Millen, Michael D. Taylor, Neurology, and Pathology

Subjects
Histone Demethylases, Otx Transcription Factors, Multidisciplinary, Core Binding Factor alpha Subunits, Muscle Proteins, Cell Differentiation, Article, Metencephalon, Repressor Proteins, Ki-67 Antigen, Cerebellum, Mutation, Humans, Cell Lineage, Hedgehog Proteins, Cerebellar Neoplasms, 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 hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. 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
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7. K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas

Author

Selin Jessa, Abdulshakour Mohammadnia, Ashot S. Harutyunyan, Maud Hulswit, Srinidhi Varadharajan, Hussein Lakkis, Nisha Kabir, Zahedeh Bashardanesh, Steven Hébert, Damien Faury, Maria C. Vladoiu, Samantha Worme, Marie Coutelier, Brian Krug, Augusto Faria Andrade, Manav Pathania, Andrea Bajic, Alexander G. Weil, Benjamin Ellezam, Jeffrey Atkinson, Roy W. R. Dudley, Jean-Pierre Farmer, Sebastien Perreault, Benjamin A. Garcia, Valérie Larouche, Mathieu Blanchette, Livia Garzia, Aparna Bhaduri, Keith L. Ligon, Pratiti Bandopadhayay, Michael D. Taylor, Stephen C. Mack, Nada Jabado, and Claudia L. Kleinman

Subjects
Epigenomics, Genetics, Brain, Cell Lineage, Article, Chromatin
Abstract

Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations, and molecular profiles. The contribution of the cell-of-origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte-precursor-like cells (OPC). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1+/SHH-dependent brainstem OPCs, while H3.3K27M gliomas frequently resemble dorsal PAX3+/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, while other epigenetic changes are mainly contingent on the cell-of-origin chromatin state and cycling rate.

Published
2022

8. Developmental Basis of SHH Medulloblastoma Heterogeneity

Author

Maxwell P. Gold, Winnie Ong, Andrew M. Masteller, Julie Anne Galindo, Noel R. Park, Raul A. Saurez, Maria C. Vladoiu, Laura K. Donovan, Adam D. Walker, Joseph Benetatos, Livia Garzia, Robert J. Wechsler-Reya, Jill P. Mesirov, Andrey Korshunov, Scott L. Pomeroy, Shawn M. Davidson, Jennifer A. Cotter, Michael D. Taylor, and Ernest Fraenkel

Abstract

Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. The sonic hedgehog (SHH) subtype accounts for 30% of MB cases and likely arises from mutations in granule cell precursors (GCPs), neuronal progenitors of the cerebellar cortex that differentiate into granule neurons. SHH MB is extremely heterogeneous, but it is unknown whether this heterogeneity relates to the tumors’ developmental origins. To investigate this question, we performed single-nucleus RNA-Sequencing on seven highly differentiated SHH MB with extensively nodular histology and observed malignant cells resembling each stage of granule neuron development. Using novel computational approaches, we connected these results to published datasets and found that established molecular subtypes of SHH MB are enriched for specific developmental cell types. Additionally, some genomic copy number variations are associated with certain developmental stages, and we observed distinct metabolic and histological profiles for tumors containing cells resembling late-stage granule neurons. This work details computational and experimental approaches that can be repurposed for analysis of tumor cell differentiation in other cancers.

Published
2022
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9. 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
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10. scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy

Author

Michael D. Taylor, Marina Sokolsky, Daniel S Malawsky, Benjamin Babcock, Duhyeong Hwang, Elias P. Rosen, Jiao Zhang, Jeremy M. Simon, Lipin Loo, Ibrahim El-Hamamy, Jennifer Ocasio, Kyle S. Smith, Rajeev Vibhakar, Mark J. Zylka, Maria C. Vladoiu, Timothy R. Gershon, Olivier Saulnier, Seth J. Weir, Taylor Dismuke, Kirk C. Wilhelmsen, Alejandro Colaneri, Paul A. Northcott, and Lincoln Stein

Subjects
0301 basic medicine, Male, Cancer therapy, Pyridines, medicine.medical_treatment, General Physics and Astronomy, Stem cell marker, Targeted therapy, Mice, 0302 clinical medicine, Single-cell analysis, Cerebellum, Cancer genomics, Anilides, Molecular Targeted Therapy, RNA-Seq, Sonic hedgehog, lcsh:Science, education.field_of_study, Multidisciplinary, Smoothened Receptor, 3. Good health, 030220 oncology & carcinogenesis, Gain of Function Mutation, Neoplastic Stem Cells, Female, Stem cell, Single-Cell Analysis, medicine.drug, Signal Transduction, Science, Population, Vismodegib, Mice, Transgenic, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Animals, Humans, Hedgehog Proteins, education, Cerebellar Neoplasms, Cell Proliferation, MyoD Protein, Medulloblastoma, General Chemistry, medicine.disease, CNS cancer, 030104 developmental biology, Drug Resistance, Neoplasm, biology.protein, Cancer research, Transcription Factor HES-1, lcsh:Q
Abstract

Targeting oncogenic pathways holds promise for brain tumor treatment, but inhibition of Sonic Hedgehog (SHH) signaling has failed in SHH-driven medulloblastoma. Cellular diversity within tumors and reduced lineage commitment can undermine targeted therapy by increasing the probability of treatment-resistant populations. Using single-cell RNA-seq and lineage tracing, we analyzed cellular diversity in medulloblastomas in transgenic, medulloblastoma-prone mice, and responses to the SHH-pathway inhibitor vismodegib. In untreated tumors, we find expected stromal cells and tumor-derived cells showing either a spectrum of neural progenitor-differentiation states or glial and stem cell markers. Vismodegib reduces the proliferative population and increases differentiation. However, specific cell types in vismodegib-treated tumors remain proliferative, showing either persistent SHH-pathway activation or stem cell characteristics. Our data show that even in tumors with a single pathway-activating mutation, diverse mechanisms drive tumor growth. This diversity confers early resistance to targeted inhibitor therapy, demonstrating the need to target multiple pathways simultaneously., Although the hedgehog (HH) pathway is known to be deregulated in medulloblastoma, inhibitors of the pathway have shown disappointing clinical benefit. Using single-cell sequencing in a mouse model of the disease, the authors show that the response to the HH pathway inhibitor vismodegib is cell-type specific.

Published
2019

11. Author Correction: Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author

Liam D. Hendrikse, Parthiv Haldipur, Olivier Saulnier, Jake Millman, Alexandria H. Sjoboen, Anders W. Erickson, Winnie Ong, Victor Gordon, Ludivine Coudière-Morrison, Audrey L. Mercier, Mohammad Shokouhian, Raúl A. Suárez, Michelle Ly, Stephanie Borlase, David S. Scott, Maria C. Vladoiu, Hamza Farooq, Olga Sirbu, Takuma Nakashima, Shohei Nambu, Yusuke Funakoshi, Alec Bahcheli, J. Javier Diaz-Mejia, Joseph Golser, Kathleen Bach, Tram Phuong-Bao, Patryk Skowron, Evan Y. Wang, Sachin A. Kumar, Polina Balin, Abhirami Visvanathan, John J. Y. Lee, Ramy Ayoub, Xin Chen, Xiaodi Chen, Karen L. Mungall, Betty Luu, Pierre Bérubé, Yu C. Wang, Stefan M. Pfister, Seung-Ki Kim, Olivier Delattre, Franck Bourdeaut, François Doz, Julien Masliah-Planchon, Wieslawa A. Grajkowska, James Loukides, Peter Dirks, Michelle Fèvre-Montange, Anne Jouvet, Pim J. French, Johan M. Kros, Karel Zitterbart, Swneke D. Bailey, Charles G. Eberhart, Amulya A. N. Rao, Caterina Giannini, James M. Olson, Miklós Garami, Peter Hauser, Joanna J. Phillips, Young S. Ra, Carmen de Torres, Jaume Mora, Kay K. W. Li, Ho-Keung Ng, Wai S. Poon, Ian F. Pollack, Enrique López-Aguilar, G. Yancey Gillespie, Timothy E. Van Meter, Tomoko Shofuda, Rajeev Vibhakar, Reid C. Thompson, Michael K. Cooper, Joshua B. Rubin, Toshihiro Kumabe, Shin Jung, Boleslaw Lach, Achille Iolascon, Veronica Ferrucci, Pasqualino de Antonellis, Massimo Zollo, Giuseppe Cinalli, Shenandoah Robinson, Duncan S. Stearns, Erwin G. Van Meir, Paola Porrati, Gaetano Finocchiaro, Maura Massimino, Carlos G. Carlotti, Claudia C. Faria, Martine F. Roussel, Frederick Boop, Jennifer A. Chan, Kimberly A. Aldinger, Ferechte Razavi, Evelina Silvestri, Roger E. McLendon, Eric M. Thompson, Marc Ansari, Maria L. Garre, Fernando Chico, Pilar Eguía, Mario Pérezpeña, A. Sorana Morrissy, Florence M. G. Cavalli, Xiaochong Wu, Craig Daniels, Jeremy N. Rich, Steven J. M. Jones, Richard A. Moore, Marco A. Marra, Xi Huang, Jüri Reimand, Poul H. Sorensen, Robert J. Wechsler-Reya, William A. Weiss, Trevor J. Pugh, Livia Garzia, Claudia L. Kleinman, Lincoln D. Stein, Nada Jabado, David Malkin, Olivier Ayrault, Jeffrey A. Golden, David W. Ellison, Brad Doble, Vijay Ramaswamy, Tamra E. Werbowetski-Ogilvie, Hiromichi Suzuki, Kathleen J. Millen, and Michael D. Taylor

Subjects
Multidisciplinary
Published
2022
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12. The transcriptional landscape of Shh medulloblastoma

Author

Jaume Mora, Erwin G. Van Meir, Olivier Delattre, Diala Abd-Rabbo, Almos Klekner, Peter Hauser, Roger E. McLendon, Amulya A. Nageswara Rao, David Malkin, James M. Olson, Boleslaw Lach, A. Sorana Morrissy, Xiaoyun Zhang, John J.Y. Lee, Steven J.M. Jones, Young Shin Ra, Ulrich Schüller, Miklós Garami, Joanna J. Phillips, Betty Luu, Hamza Farooq, Johan M. Kros, Karel Zitterbart, Michael K. Cooper, Raul Suarez, William A. Weiss, Quang M. Trinh, Ana Guerreiro Stucklin, Tomoko Shofuda, Carmen de Torres, Marco A. Marra, Enrique López-Aguilar, Hiromichi Suzuki, Patryk Skowron, Eric Bouffet, Karen Mungall, Evan Y. Wang, Tina Zheng, Maria C. Vladoiu, Julien Masliah-Planchon, Ian F. Pollack, Wai Sang Poon, Liam D. Hendrikse, Claudia C. Faria, Yu Chang Wang, Kay Ka Wai Li, Carlos Gilberto Carlotti, Joshua B. Rubin, Gary D. Bader, Aaron Gillmor, Caterina Giannini, Uri Tabori, Shin Jung, Franck Bourdeaut, Chi-chung Hui, Avesta Rastan, Reid C. Thompson, Jennifer A. Chan, Nada Jabado, David Meyronet, Rajeev Vibhakar, Jiannis Ragoussis, Michelle Ly, Olivier Ayrault, Charles G. Eberhart, Andrew J. Mungall, Wiesława Grajkowska, Xiaochong Wu, Jüri Reimand, Ho Keung Ng, Vernon Fong, Michael D. Taylor, Seung-Ki Kim, Florence M.G. Cavalli, Carolina Nor, Helen He Zhu, Eric M. Thompson, Borja L. Holgado, David Zagzag, Craig Daniels, Gelareh Zadeh, Haig Djambazian, G. Yancey Gillespie, Peter B. Dirks, Richard A. Moore, John A. Calarco, Shizhong Dai, Vijay Ramaswamy, Lincoln Stein, Pierre Bérubé, Pim J. French, Toshihiro Kumabe, James Loukides, Swneke D. Bailey, Linda M. Liau, Ronald L. Hamilton, Francois P. Doz, Maria Luisa Garrè, László Bognár, The Hospital for sick children [Toronto] (SickKids), The Wellcome Trust Sanger Institute [Cambridge], Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurology, Pathology, Repositório da Universidade de Lisboa, Skowron, Patryk, Farooq, Hamza, Cavalli, Florence M G, Morrissy, A Sorana, Ly, Michelle, Hendrikse, Liam D, Wang, Evan Y, Djambazian, Haig, Zhu, Helen, Mungall, Karen L, Trinh, Quang M, Zheng, Tina, Dai, Shizhong, Stucklin, Ana S Guerreiro, Vladoiu, Maria C, Fong, Vernon, Holgado, Borja L, Nor, Carolina, Wu, Xiaochong, Abd-Rabbo, Diala, Bérubé, Pierre, Wang, Yu Chang, Luu, Betty, Suarez, Raul A, Rastan, Avesta, Gillmor, Aaron H, Lee, John J Y, Zhang, Xiao Yun, Daniels, Craig, Dirks, Peter, Malkin, David, Bouffet, Eric, Tabori, Uri, Loukides, Jame, Doz, François P, Bourdeaut, Franck, Delattre, Olivier O, Masliah-Planchon, Julien, Ayrault, Olivier, Kim, Seung-Ki, Meyronet, David, Grajkowska, Wieslawa A, Carlotti, Carlos G, de Torres, Carmen, Mora, Jaume, Eberhart, Charles G, Van Meir, Erwin G, Kumabe, Toshihiro, French, Pim J, Kros, Johan M, Jabado, Nada, Lach, Boleslaw, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Olson, James M, Bognár, László, Klekner, Almo, Zitterbart, Karel, Phillips, Joanna J, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Liau, Linda M, Garami, Mikló, Hauser, Peter, Li, Kay Ka Wai, Ng, Ho-Keung, Poon, Wai Sang, Yancey Gillespie, G, Chan, Jennifer A, Jung, Shin, McLendon, Roger E, Thompson, Eric M, Zagzag, David, Vibhakar, Rajeev, Ra, Young Shin, Garre, Maria Luisa, Schüller, Ulrich, Shofuda, Tomoko, Faria, Claudia C, López-Aguilar, Enrique, Zadeh, Gelareh, Hui, Chi-Chung, Ramaswamy, Vijay, Bailey, Swneke D, Jones, Steven J, Mungall, Andrew J, Moore, Richard A, Calarco, John A, Stein, Lincoln D, Bader, Gary D, Reimand, Jüri, Ragoussis, Jianni, Weiss, William A, Marra, Marco A, Suzuki, Hiromichi, and Taylor, Michael D

Subjects
0301 basic medicine, Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Physics and Astronomy, ComputingMilieux_LEGALASPECTSOFCOMPUTING, Genome informatics, Transcriptome, 0302 clinical medicine, Genetics research, 2.1 Biological and endogenous factors, Gene Regulatory Networks, Sonic hedgehog, Aetiology, Child, Cancer, Regulation of gene expression, Pediatric, Multidisciplinary, Gene Regulatory Network, biology, Middle Aged, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Child, Preschool, embryonic structures, Female, TRANSDUÇÃO DE SINAL CELULAR, Hedgehog Protein, Human, Signal Transduction, Biotechnology, Adult, Pediatric Research Initiative, animal structures, Adolescent, Pediatric Cancer, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Article, General Biochemistry, Genetics and Molecular Biology, Paediatric cancer, 03 medical and health sciences, Young Adult, Rare Diseases, SDG 3 - Good Health and Well-being, Clinical Research, GLI2, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], GNAS complex locus, medicine, Genetics, Humans, Hedgehog Proteins, Cerebellar Neoplasms, Preschool, neoplasms, Gene, Medulloblastoma, Neoplastic, Cerebellar Neoplasm, Human Genome, Neurosciences, Infant, Genetic Variation, General Chemistry, medicine.disease, Brain Disorders, CNS cancer, Brain Cancer, 030104 developmental biology, PTCH1, Gene Expression Regulation, biology.protein
Abstract

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention., Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

Published
2021
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13. An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate

Author

Ludivine Coudière Morrison, Jennifer A. Chan, Margaret Stromecki, Gareth A. Palidwor, Maria C. Vladoiu, Cynthia Hawkins, Jamie Zagozewski, Tamra E. Werbowetski-Ogilvie, Ghazaleh M. Shahriary, Janilyn Arsenio, Olivier Ayrault, Lakshmikirupa Sundaresan, Vijay Ramaswamy, Antoine Forget, Agnes Fresnoza, Christopher J. Porter, Michael D. Taylor, Olivier Saulnier, University of Manitoba [Winnipeg], The Hospital for sick children [Toronto] (SickKids), Ottawa Hospital Research Institute [Ottawa] (OHRI), Institut Curie [Orsay], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (PSL), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), University of Toronto, University of Calgary, Manitoba Centre for Proteomics and Systems Biology [Winnipeg, MB, Canada], This work was funded by a Project Grant from the Canadian Institutes of Health Research (CIHR), and an Innovation Grant from Alex’s Lemonade Stand Foundation (to T.E.W.-O.). V.R. is supported by CIHR, the American Brain Tumor Association, the Garron Family Cancer Center, and the C.R. Younger Foundation. J.Z. was supported by a joint Postdoctoral Fellowship from the CancerCare Manitoba Foundation, the Children’s Hospital Research Institute of Manitoba and Research Manitoba., and Bodescot, Myriam

Subjects
0301 basic medicine, PAX6 Transcription Factor, Carcinogenesis, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell, General Physics and Astronomy, 0302 clinical medicine, lcsh:Science, Regulation of gene expression, Multidisciplinary, Otx Transcription Factors, Cancer stem cells, Cell Differentiation, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Signal Transduction, Science, Tumour heterogeneity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell fate determination, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer stem cell, Cell Line, Tumor, medicine, Gene silencing, Animals, Humans, Cerebellar Neoplasms, Transcription factor, neoplasms, PAX3 Transcription Factor, Cell Proliferation, Medulloblastoma, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Chemistry, Oncogenes, medicine.disease, nervous system diseases, CNS cancer, stomatognathic diseases, 030104 developmental biology, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Cancer research, lcsh:Q, PAX6
Abstract

OTX2 is a potent oncogene that promotes tumor growth in Group 3 medulloblastoma. However, the mechanisms by which OTX2 represses neural differentiation are not well characterized. Here, we perform extensive multiomic analyses to identify an OTX2 regulatory network that controls Group 3 medulloblastoma cell fate. OTX2 silencing modulates the repressive chromatin landscape, decreases levels of PRC2 complex genes and increases the expression of neurodevelopmental transcription factors including PAX3 and PAX6. Expression of PAX3 and PAX6 is significantly lower in Group 3 medulloblastoma patients and is correlated with reduced survival, yet only PAX3 inhibits self-renewal in vitro and increases survival in vivo. Single cell RNA sequencing of Group 3 medulloblastoma tumorspheres demonstrates expression of an undifferentiated progenitor program observed in primary tumors and characterized by translation/elongation factor genes. Identification of mTORC1 signaling as a downstream effector of OTX2-PAX3 reveals roles for protein synthesis pathways in regulating Group 3 medulloblastoma pathogenesis., OTX2 promotes tumour growth in Group 3 medulloblastoma. Here, the authors show that OTX2 regulates PAX3 to induce neural de-differentiation and promote tumourigenesis in Group 3 medulloblastoma.

Published
2020
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14. Spatial heterogeneity in medulloblastoma

Author

David T.W. Jones, Yusanne Ma, Xin Wang, Betty Luu, Cynthia Hawkins, Adrian Ally, Marc Remke, John S. Myseros, Nada Jabado, Adam M. Fontebasso, Volker Hovestadt, Michael D. Taylor, Craig Daniels, Borja L. Holgado, Steffen Albrecht, Uri Tabori, David Malkin, Andrey Korshunov, Diana M. Merino, Stuart Horswell, Rebecca Carlsen, James T. Rutka, Daniel Picard, Marco A. Marra, David Shih, Angela Tam, Patrick Plettner, Roger J. Packer, Gary D. Bader, Erin N. Kiehna, Hamza Farooq, Eloi Mercier, John Peacock, Stephen C. Mack, A. Sorana Morrissy, Sameer Agnihotri, Jonathon Torchia, Vijay Ramaswamy, Young Cheng, Kane Tse, Steven J.M. Jones, Laura K. Donovan, Richard A. Moore, Sunit Das, Annie Huang, Nina Thiessen, James Loukides, Darlene Lee, Yisu Li, Marcel Kool, Charles Swanton, Eric Chuah, Tenzin Gayden, Xiaochong Wu, Michael Mayo, Eric Bouffet, Chelsea Mayoh, Peter Lichter, Noreen Dhalla, Brian R. Rood, Jacek Majewski, Ulrich Schüller, Haiyan I. Li, Richard Corbett, Tina Wong, Paul A. Northcott, Pawel Buczkowicz, Florence M.G. Cavalli, Yuan Yao Thompson, William Long, Maria C. Vladoiu, Peter B. Dirks, Hamid Nikbakht, Livia Garzia, Stefan M. Pfister, Jacqueline E. Schein, Simon Papillon-Cavanagh, Andrew J. Mungall, and Jüri Reimand

Subjects
Adult, Male, 0301 basic medicine, renal cell carcinoma, DNA Copy Number Variations, Genome-wide association study, Biology, medulloblastoma, Bioinformatics, Polymorphism, Single Nucleotide, Article, whole exome sequencing, Genetic Heterogeneity, glioblastoma multiforme, 03 medical and health sciences, INDEL Mutation, Renal cell carcinoma, Glioma, Biopsy, gene expression profiling, Genetics, medicine, Cluster Analysis, Humans, Cerebellar Neoplasms, Child, Aged, Aged, 80 and over, Medulloblastoma, Principal Component Analysis, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, business.industry, Genetic heterogeneity, Middle Aged, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, Gene expression profiling, 030104 developmental biology, Child, Preschool, Mutation, Cancer research, Female, Spatial heterogeneity, Personalized medicine, Transcriptome, business, Genome-Wide Association Study
Abstract

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Published
2017
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15. 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

16. Stalled developmental programs at the root of pediatric brain tumors

Author

Nicolas De Jay, Gustavo Turecki, Florence M.G. Cavalli, Yixing Hu, Alexis Blanchet-Cohen, Corina Nagy, W. Todd Farmer, Andréa Allaire, Hervé Sartelet, Louis Crevier, Roy W. R. Dudley, Jiannis Ragoussis, Marie Coutelier, Maxime Richer, Maria C. Vladoiu, Livia Garzia, Michael D. Taylor, Claudia L. Kleinman, Valerie Larouche, Jean Monlong, Jeffrey Atkinson, Nada Jabado, Guillaume Bourque, Laura K. Donovan, Keith K. Murai, Benjamin Ellezam, Pierre-Eric Lutz, Jean-Pierre Farmer, Brice Poreau, Leonie G. Mikael, Alexander G. Weil, Mariella G. Filbin, Steven Hébert, Selin Jessa, Santiago Costantino, Steffen Albrecht, Damien Faury, Peter B. Dirks, Brian Krug, Melissa K. McConechy, McGill University = Université McGill [Montréal, Canada], Lady Davis Institute for Medical Research [Montréal], McGill University = Université McGill [Montréal, Canada]-Jewish General Hospital, The Hospital for sick children [Toronto] (SickKids), McGill University Health Center [Montreal] (MUHC), Centre Hospitalier Universitaire [Grenoble] (CHU), Santa Cruz Genomics Institute, University of California [Santa Cruz] (UCSC), University of California-University of California, Zebralog GmbH & Co. KG, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry [Montréal], Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal General Hospital, McGill University and Genome Quebec Innovation Centre, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], This work was supported by funding from: a Large-Scale Applied Research Project grant from Genome Quebec, Genome Canada, the Government of Canada and the Ministère de l'Économie, de la Science et de l’Innovation du Québec, with the support of the Ontario Research Fund through funding provided by the Government of Ontario to N.J., M.D.T., C.L.K., P.B.D., G.B., J.R. and L.G., the Canadian Institutes for Health Research (CIHR grant nos. PJT-156086, to C.L.K., and MOP-286756 and FDN-154307, to N.J.), the US National Institutes of Health (NIH grant nos. P01-CA196539, to N.J., R01CA148699 and R01CA159859, to M.D.T.), the Canadian Cancer Society (CCSRI grant no. 705182), NSERC (grant no. RGPIN-2016-04911) and the Fonds de Recherche du Québec en Santé (FRQS) salary award to C.L.K., National Sciences and Engineering Research Council (grant no. NSERC-448167-2013) and FRQS (grant no. 25348) to G.B., CFI Leaders Opportunity Fund (grant nos. 32557, to J.R., and 33902, to C.L.K.), Genome Canada Science Technology Innovation Centre, Compute Canada Resource Allocation Project (grant no. WST-164-AB) and Genome Canada Genome Innovation Node (grant no. 244819) to J.R., and and the Fondation Charles-Bruneau. Data analyses were enabled by computer and storage resources provided by Compute Canada and Calcul Québec. N.J. is a member of the Penny Cole Laboratory and the recipient of a Chercheur Boursier, Chaire de Recherche Award from the FRQS. This work was performed within the context of the International Childhood Astrocytoma Integrated Genomic and Epigenomic (ICHANGE) consortium, and the Stand Up to Cancer (SU2C) Canada Cancer Stem Cell Dream Team Research Funding (grant no. SU2C-AACR-DT-19-15, to M.D.T. and N.J.) and SU2C St. Baldrick’s Pediatric Dream Team Translational Research Grant (no. SU2C-AACR-DT1113, to M.D.T.), with funding from Genome Canada and Genome Quebec. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is supported by The Pediatric Brain Tumour Foundation, The Canadian Institutes of Health Research, The Cure Search Foundation, b.r.a.i.n.child, Meagan’s Walk, SWIFTY Foundation, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, V-Foundation for Cancer Research, Cancer Research UK Brain Tumour Award, Canadian Cancer Society Research Institute Impact grant and the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. S.J. is supported by a fellowship from CIHR. A.B.-C. is supported by a fellowship from FRQS and TD/LDI. N.D.J. is a recipient of a fellowship from FRQS and RMGA. M.K.M. is funded by a CIHR Banting postdoctoral fellowship. We thank K. Mann, S. Spira and J. Di Noia for critical reading of the manuscript, and S. Krumholtz for graphical editing of figures. We are especially grateful for the generous philanthropic donations of the Fondation Charles-Bruneau, and the Kat D-DIPG, Poppies for Irina and We Love You Connie Foundations.

Subjects
[SDV]Life Sciences [q-bio], Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Transcriptome, Mice, 03 medical and health sciences, Nerve Fibers, Prosencephalon, 0302 clinical medicine, Single-cell analysis, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Progenitor cell, Rhabdoid Tumor, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Neuroectoderm, Brain Neoplasms, Wnt signaling pathway, Brain, Gene Expression Regulation, Developmental, Infant, Neoplasms, Germ Cell and Embryonal, 3. Good health, medicine.anatomical_structure, Forebrain, Single-Cell Analysis, Neuroscience, 030217 neurology & neurosurgery, Medulloblastoma
Abstract

International audience; Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.

Published
2019
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17. Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse

Author

Jiao Zhang, Andrew S. Potter, W. Clay Gustafson, Liguo Zhang, Feng Zhang, Scott L. Pomeroy, Maryam Fouladi, Martine F. Roussel, Allison Pribnow, Xuezhao Liu, Michael D. Taylor, Kalen P. Berry, Q. Richard Lu, Lingli Xu, Blaise V. Jones, Christine Fuller, Maria C. Vladoiu, James M. Olson, Emily J. Girard, Weidong Tian, Marc Remke, Tao Zheng, S. Steven Potter, Xuelian He, Mei Xin, Wenhao Zhou, A. Sorana Morrissy, Rachid Drissi, Zaili Luo, Stephanie M.C. Smith, William A. Weiss, L. Frank Huang, and Zeng-Jie Yang

Subjects
0301 basic medicine, Male, Cancer Research, Datasets as Topic, Tumor initiation, medicine.disease_cause, Cell Transformation, Transgenic, Transcriptome, Mice, 0302 clinical medicine, Stem Cell Research - Nonembryonic - Human, 2.1 Biological and endogenous factors, Gene Regulatory Networks, RNA-Seq, Sonic hedgehog, Aetiology, Child, Cancer, Pediatric, Tumor, Brain Neoplasms, AURORA-A/MYCN, OPC-like, Prognosis, HIPPO-YAP/TAZ, glial progenitors, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Oncology, Local, progenitor heterogeneity, 030220 oncology & carcinogenesis, Child, Preschool, Gene Knockdown Techniques, Neoplastic Stem Cells, Female, Stem Cell Research - Nonembryonic - Non-Human, Single-Cell Analysis, Neuroglia, Signal Transduction, Biotechnology, OLIG2, Oncology and Carcinogenesis, Mice, Transgenic, Biology, Cell Line, 03 medical and health sciences, Rare Diseases, Cell Line, Tumor, medicine, Genetics, Animals, Humans, Hedgehog Proteins, recurrent tumors, Oncology & Carcinogenesis, Progenitor cell, Preschool, Progenitor, Cell Proliferation, Medulloblastoma, Neoplastic, Animal, medulloblastomas, Human Genome, Neurosciences, Oligodendrocyte Transcription Factor 2, medicine.disease, Stem Cell Research, Survival Analysis, Brain Disorders, Brain Cancer, Disease Models, Animal, 030104 developmental biology, Neoplasm Recurrence, Gene Expression Regulation, Disease Models, Cancer research, biology.protein, sonic hedgehog (SHH) signaling, Neoplasm Recurrence, Local, Carcinogenesis, single-cell transcriptomics
Abstract

Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) medulloblastomas, and identified OLIG2-expressing glial progenitors as transit-amplifying cells at the tumorigenic onset. Although OLIG2+ progenitors become quiescent stem-like cells in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. Depletion of mitotic Olig2+ progenitors or Olig2 ablation impeded tumor initiation. Genomic profiling revealed that OLIG2 modulates chromatin landscapes and activates oncogenic networks including HIPPO-YAP/TAZ and AURORA-A/MYCN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results indicate that glial lineage-associated OLIG2+ progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting OLIG2-driven oncogenic networks as potential therapeutic targets.

Published
2019

18. 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

19. Medulloblastoma Arises from the Persistence of a Rare and Transient Sox2

Author

Hayden J, Selvadurai, Erika, Luis, Kinjal, Desai, Xiaoyang, Lan, Maria C, Vladoiu, Owen, Whitley, Ciaran, Galvin, Robert J, Vanner, Lilian, Lee, Heather, Whetstone, Michelle, Kushida, Tomasz, Nowakowski, Phedias, Diamandis, Cynthia, Hawkins, Gary, Bader, Arnold, Kriegstein, Michael D, Taylor, and Peter B, Dirks

Subjects
Male, Mice, Knockout, Neurons, Neurogenesis, SOXB1 Transcription Factors, Mice, Transgenic, Neural Stem Cells, Cerebellum, Animals, Humans, Cell Lineage, Female, Hedgehog Proteins, Neoplasm Recurrence, Local, Single-Cell Analysis, Cerebellar Neoplasms, Cells, Cultured, Medulloblastoma, Signal Transduction
Abstract

Medulloblastoma (MB) is a neoplasm linked to dysregulated cerebellar development. Previously, we demonstrated that the Sonic Hedgehog (SHH) subgroup grows hierarchically, with Sox2

Published
2019

20. MEDU-40. MATCHING OF SINGLE CELL TRANSCRIPTOMICS FROM CEREBELLAR DEVELOPMENT IDENTIFIES PUTATIVE SUBGROUP SPECIFIC CELLS OF ORIGIN FOR MEDULLOBLASTOMA

Author

Alexandra L. Joyner, Borja L Holgado, Florence Cavalli, Hamza Farooq, Jennifer A. Chan, Michael D. Taylor, Claudia L. Kleinman, Betty Luu, Nada Jabado, Laura K. Donovan, Lincoln Stein, Maria C. Vladoiu, Vijay Ramaswamy, and Ibrahim El-Hamamy

Subjects
0301 basic medicine, Medulloblastoma, Cancer Research, Cerebellum, Nestin protein, Single cell transcriptomics, fungi, Embryo, Computational biology, Biology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, medicine, Neurology (clinical), Stem cell, Rhombic lip, 030217 neurology & neurosurgery
Abstract

We isolated cells from various points in murine embryonic and early post-ntal cerebellar development (E10 to P14) and undertook single cell RNA sequencing to identify >30 transcriptionally distinct cell populations. Reconstruction of developmental lineages in the developing cerebellum through pseudotemporal analysis demonstrate that a progenitor cell population from the upper rhombic lip gives rise to both the external granule cell layer (EGL) and the previously under-studied unipolar brush cells (UBC). Unipolar brush cells are a glutamatergic interneuron most prevalent in the inferior and lateral cerebellum. Transcriptional matching of bulk human tumor RNA-seq data from human patients demonstrates subgroup specific transcriptional resemblances. As expected, Shh MBs resemble the developing EGL. Fascinatingly, only Shh tumors that transcriptionally mirror earlier, but not later EGL developmental time points were found to be metastatic in human patients. Group 3 tumors have a resemblance to early Nestin +ve stem cells across the entire subgroup, with additional similarities to the EGL, UBC, and GABAergic interneurons. Unexpectedly, Group 4 tumors were vastly most similar to UBCs, and on further analysis to a single known subset of UBCs (Calb2+ve UBCs). Single cell RNA-seq from human medulloblastomas (Shh, Group 3, and Group 4 MB) largely confirms the transcriptional similarities to murine cerebellar developmental lineages observed in the bulk RNA-seq data, but also demonstrates that most medulloblastomas have multiple distinct tumor cell clusters. Distinct single cell expression clusters from an individual MB demonstrate that there is a developmental lineage or hierarchy of cells with most tumors, that this hierarchy is likely hardwired from normal development, and that bulk tumor data in fact reflects a heterogeneous cell population. These data pinpoint possible cells of origin for medulloblastoma subgroups, illustrate a further layer of MB heterogeneity, and allow a comparison of normal and MB transcriptomes to further understand MB biology.

Published
2019

21. TBIO-15. MODELING DEVELOPMENTAL GENE EXPRESSION DYNAMICS AT CELLULAR RESOLUTION TO INTERPRET PEDIATRIC BRAIN TUMOR TRANSCRIPTIONAL PROGRAMS

Author

Selin Jessa, Steven Hébert, Maria C. Vladoiu, Nada Jabado, Michael D. Taylor, Claudia L. Kleinman, and Nisha Kabir

Subjects
Cancer Research, Cellular differentiation, Dynamics (mechanics), Computational biology, Biology, medicine.disease_cause, Oncology, Cellular resolution, Gene expression, Pediatric Brain Tumor, medicine, AcademicSubjects/MED00300, AcademicSubjects/MED00310, Neurology (clinical), Carcinogenesis, Transcription factor, Gene, Tumor Biology (not fitting a specific disease category)
Abstract

A central challenge in understanding the biology of pediatric brain tumors is defining the cellular and molecular context where oncogenesis occurs. We hypothesize that spatiotemporally restricted cell types are uniquely susceptible to specific genetic alterations, which alter normal neurodevelopmental programs and ultimately lead to oncogenesis. The resulting tumors retain some transcriptomic features of their lineage of origin. To delineate these origins, we assembled a densely sampled developmental time course of the mouse forebrain and pons, doubling our recently published single-cell atlas. This dataset comprises >100,000 cells at 9 timepoints from E10-P6. However, while single cell transcriptomics reveal rich gene dynamics during cell differentiation, interpretation of individual genes can be challenging due to data sparsity. Leveraging this time-series, we present strategies to model and visualize the expression of a given gene across differentiation of distinct lineages. We demonstrate an interactive web app to interrogate the expression of genes or gene sets during brain development, extract temporally correlated genes, and search active transcription factor regulatory modules. Finally, we profile the expression of core transcriptional programs of several pediatric brain tumor entities during development. Our analyses reveal genes with restricted expression patterns that elucidate tumor etiology. More broadly, these resources harness single cell data to enable exploration of neurodevelopmental gene programs with great relevance to pediatric brain tumor oncogenesis.

Published
2020

22. 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

23. Medulloblastoma Arises from the Persistence of a Rare and Transient Sox2+ Granule Neuron Precursor

Author

Cynthia Hawkins, Michael D. Taylor, Maria C. Vladoiu, Ciaran Galvin, Erika Luis, Peter B. Dirks, Kinjal Desai, Arnold R. Kriegstein, Gary D. Bader, Phedias Diamandis, Tomasz J. Nowakowski, Hayden J. Selvadurai, Lilian Lee, Xiaoyang Lan, Robert Vanner, Michelle Kushida, Owen Whitley, and Heather Whetstone

Subjects
0301 basic medicine, Medulloblastoma, education.field_of_study, animal structures, fungi, Population, Tumor initiation, Biology, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Neural stem cell, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, SOX2, Cancer stem cell, Tumor progression, embryonic structures, medicine, biology.protein, Sonic hedgehog, education, 030217 neurology & neurosurgery
Abstract

Medulloblastoma (MB) is a neoplasm linked to dysregulated cerebellar development. Previously, we demonstrated that the Sonic Hedgehog (SHH) subgroup grows hierarchically, with Sox2+ cells at the apex of tumor progression and relapse. To test whether this mechanism is rooted in a normal developmental process, we studied the role of Sox2 in cerebellar development. We find that the external germinal layer (EGL) is derived from embryonic Sox2+ precursors and that the EGL maintains a rare fraction of Sox2+ cells during the first postnatal week. Through lineage tracing and single-cell analysis, we demonstrate that these Sox2+ cells are within the Atoh1+ lineage, contribute extensively to adult granule neurons, and resemble Sox2+ tumor cells. Critically, constitutive activation of the SHH pathway leads to their aberrant persistence in the EGL and rapid tumor onset. We propose that failure to eliminate this rare but potent developmental population is the tumor initiation mechanism in SHH-subgroup MB.

Published
2020
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24. 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

25. 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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26. PDTM-28. AN OTX2-PAX3 SIGNALLING AXIS REGULATES GROUP 3 MEDULLOBLASTOMA CELL FATE

Author

Antoine Forget, Michael D. Taylor, Jamie Zagozewski, Jennifer A. Chan, Tamra E. Werbowetski-Ogilvie, Cynthia Hawkins, Agnes Fresnoza, Gareth A. Palidwor, Ludivine Coudière Morrison, Olivier Saulnier, Olivier Ayrault, Christopher J. Porter, Margaret Stromecki, Vijay Ramaswamy, Maria C. Vladoiu, and Ghazaleh M. Shahriary

Subjects
Medulloblastoma, Cancer Research, Pediatric Tumors, Chemistry, PAX3, mTORC1, Cell cycle, Cell fate determination, medicine.disease, Cell biology, Chromatin, Oncology, Cell culture, medicine, Neurology (clinical), Signal transduction
Abstract

The majority of Group 3 medulloblastomas (MB) exhibit amplification or increased expression of OTX2. OTX2 is primarily known as an oncogenic driver of tumor growth and cell cycle progression in Group 3 MB; however, its role as a repressor of differentiation is poorly characterized. Therefore, we utilized extensive patient data and mapped Group 3 MB chromatin dynamics in stem cell-enriched cultures to evaluate the divergent role of OTX2 in cell fate decisions in Group 3 MB pathogenesis. Several PAX genes were identified as novel OTX2 targets in Group 3 MB. Examination of patient data revealed that PAX3 and PAX6 expression is significantly reduced in Group 3 MB patients and is associated with significantly reduced survival. Functional evaluation of PAX3 and PAX6 expression showed that PAX3 expression significantly reduced self-renewal capacity of Group 3 MB tumorspheres in vitro and significantly prolonged survival and reduced tumor size in orthotopic xenograft models in vivo. RNA-sequencing of PAX3 and PAX6 gain of function (GOF) tumorspheres revealed mTORC1 signalling was specifically downregulated in PAX3 GOF, indicating this pathway may be critical for the survival and self-renewal differences observed between PAX3/PAX6 GOF models. Treatment of Group 3 MB with mTOR inhibitors reduced self-renewal in vitro and significantly prolonged survival and reduced tumor size in vivo. To further evaluate the role for this signalling axis in the Group 3 MB neural lineage hierarchy, we carried out scRNA-sequencing in tumorspheres from 4 Group 3 MB cell lines. Interestingly, a broad range of OTX2 expression was observed across single cell clusters, suggesting distinct OTX2 regulatory hierarchies are present in Group 3 MB. Collectively, our work demonstrates the multifaceted role of OTX2 as a regulator of cell fate decisions in Group 3 MB and identifies a novel role for mTORC1 signalling in Group 3 MB self-renewal and differentiation.

Published
2019
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27. GENE-21. A COMMON FETAL DEVELOPMENTAL ORIGIN FOR PFA EPENDYMOMA, PFB EPENDYMOMA, AND CEREBELLAR PILOCYTIC ASTROCYTOMAS?

Author

Maria C. Vladoiu, Jennifer A. Chan, Hamza Farooq, Faiyaz Notta, Sheila K. Singh, Vijay Ramaswamy, Ibrahim El-Hamamy, Laura K. Donovan, Lincoln Stein, Borja Holgado Lopez, Nada Jabado, Michael D. Taylor, and Claudia L. Kleinman

Subjects
Ependymoma, Cancer Research, Cerebellum, Fetus, Pathology, medicine.medical_specialty, Pilocytic astrocytoma, Biology, medicine.disease, Abstracts, medicine.anatomical_structure, Oncology, Infratentorial Neoplasm, embryonic structures, medicine, Neuroglia, Neurology (clinical), Stem cell, Rhombic lip
Abstract

Single cell RNA-sequencing (scRNAseq) of murine cerebellum at nine fetal and immediate post-natal (E10-P14) times points on >60,000 individual cells to identified >30 transcriptionally distinct cell clusters. Based on marker gene expression, many clusters resemble known cerebellar stem, progenitor, and differentiated cell types, while other clusters are more novel. Pseudo-time trajectory assisted in the reconstruction of known and novel developmental lineages, including the lineage of the cerebellar radial glia. A population of stem cells in the ventricular zone (VZ) gives rise to the progenitors of the GABAergic cerebellar interneurons, as well as the gliogenic progenitor cells, which subsequently become Bergmann glia and astrocytes. A novel, but clearly distinct and robust cluster of cells with transcriptional similarity to both the roof plate and the rhombic lip was identified. Comparison of bulk RNA-seq from human PFA, PFB, and cerebellar pilocytic astrocytomas (C-PA) reveals that all three-tumor types best transcriptionally match the gliogenic progenitor cells, with some similarity to VZ stem cells and the ‘roof plate like’ stem cells. Furthermore, all three tumor types are transcriptionally much more similar to the gliogenic progenitors at E16 than at E14 or E18. Subclustering of gliogenic progenitors reveals significant intra-cluster heterogeneity, with the ependymomas transcriptionally matching one subcluster, and the C-PA clearly matching a very different subcluster. scRNAseq of human PFA and PFB ependymomas reveals multiple tumor cell clusters within a given human ependymoma, with some clusters matching most closely to the gliogenic progenitors, and others matching best to the ‘roof plate like’ stem cells. Similarity to the ‘roof plate stem cells’ (E10-E14), and gliogenic progenitors (E14-E18) suggests an embryonic origin for PFA, PFB, and C-PA, suggests specific novel cells of origin, and offers a novel opportunity to understand posterior fossa tumor transcriptomic targets for novel therapy.

Published
2018
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