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1. 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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2. Identification of a Novel Gammaherpesvirus in Canada lynx (Lynx canadensis)

Author

Liam D. Hendrikse, Ankita Kambli, Caroline Kayko, Marta Canuti, Bruce Rodrigues, Brian Stevens, Jennifer Vashon, Andrew S. Lang, David B. Needle, and Ryan M. Troyer

Subjects
herpesvirus, virus, felid, cat, phylogenetic, Percavirus, DNA polymerase, glycoprotein B, lynx, Microbiology, QR1-502
Abstract

Gammaherpesviruses (GHVs) infect many animal species and are associated with lymphoproliferative disorders in some. Previously, we identified several novel GHVs in North American felids; however, a GHV had never been identified in Canada lynx (Lynx canadensis). We, therefore, hypothesized the existence of an unidentified GHV in lynx. Using degenerate nested and subsequently virus-specific PCR, we amplified and sequenced 3.4 kb of DNA from a novel GHV in lynx, which we named Lynx canadensis gammaherpesvirus 1 (LcaGHV1). Phylogenetic analysis determined that LcaGHV1 is a distinct GHV species belonging to the genus Percavirus. We then estimated the prevalence of LcaGHV1 in lynx by developing a PCR-based assay and detected LcaGHV1 DNA in 36% (95% CI: 22–53%) of lynx spleen DNA samples from Maine, USA and 17% (95% CI: 8–31%) from Newfoundland, Canada. The LcaGHV1 DNA sequences from Maine and Newfoundland lynx were nearly identical to each other (two nucleotide substitutions in 3.4 kb), suggesting that the unique lynx subspecies present on the island of Newfoundland (Lynx canadensis subsolanus) is infected with virus that very closely resembles virus found in mainland lynx. The potential ecologic and pathologic consequences of this novel virus for Canada lynx populations warrant further study.

Published
2019
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3. 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

4. Table S2 from H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone

Author

Nada Jabado, Claudia L. Kleinman, Livia Garzia, Michael D. Taylor, Stephen C. Mack, Benjamin A. Garcia, Peter W. Lewis, Pierre Thibault, Jay S. Wunder, Robert Turcotte, Brendan C. Dickson, Jason Karamchandani, Sungmi Jung, Ashot S. Harutyunyan, Véronique Lisi, Robert Eveleigh, Tianna S. Sihota, Kateryna Rossokhata, Siddhant U. Jain, Takeaki Ishii, Éric Bonneil, Joel Lanoix, Dylan M. Marchione, Damien Faury, Leonie G. Mikael, Carol C.L. Chen, Wajih Jawhar, Liam D. Hendrikse, Shriya Deshmukh, Nicolas De Jay, and Sima Khazaei

Abstract

Differential Expression in Isogenic Lines

Published
2023

5. Data from H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone

Author

Nada Jabado, Claudia L. Kleinman, Livia Garzia, Michael D. Taylor, Stephen C. Mack, Benjamin A. Garcia, Peter W. Lewis, Pierre Thibault, Jay S. Wunder, Robert Turcotte, Brendan C. Dickson, Jason Karamchandani, Sungmi Jung, Ashot S. Harutyunyan, Véronique Lisi, Robert Eveleigh, Tianna S. Sihota, Kateryna Rossokhata, Siddhant U. Jain, Takeaki Ishii, Éric Bonneil, Joel Lanoix, Dylan M. Marchione, Damien Faury, Leonie G. Mikael, Carol C.L. Chen, Wajih Jawhar, Liam D. Hendrikse, Shriya Deshmukh, Nicolas De Jay, and Sima Khazaei

Abstract

Glycine 34-to-tryptophan (G34W) substitutions in H3.3 arise in approximately 90% of giant cell tumor of bone (GCT). Here, we show H3.3 G34W is necessary for tumor formation. By profiling the epigenome, transcriptome, and secreted proteome of patient samples and tumor-derived cells CRISPR–Cas9-edited for H3.3 G34W, we show that H3.3K36me3 loss on mutant H3.3 alters the deposition of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes redistribution of other chromatin marks and aberrant transcription, altering cell fate in mesenchymal progenitors and hindering differentiation. Single-cell transcriptomics reveals that H3.3 G34W stromal cells recapitulate a neoplastic trajectory from a SPP1+ osteoblast-like progenitor population toward an ACTA2+ myofibroblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3 G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors, which promotes neoplastic growth, pathologic recruitment of giant osteoclasts, and bone destruction.Significance:This study shows that H3.3 G34W drives GCT tumorigenesis through aberrant epigenetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interactions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT.See related commentary by Licht, p. 1794.This article is highlighted in the In This Issue feature, p. 1775

Published
2023

6. Supplementary Figures from H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone

Author

Nada Jabado, Claudia L. Kleinman, Livia Garzia, Michael D. Taylor, Stephen C. Mack, Benjamin A. Garcia, Peter W. Lewis, Pierre Thibault, Jay S. Wunder, Robert Turcotte, Brendan C. Dickson, Jason Karamchandani, Sungmi Jung, Ashot S. Harutyunyan, Véronique Lisi, Robert Eveleigh, Tianna S. Sihota, Kateryna Rossokhata, Siddhant U. Jain, Takeaki Ishii, Éric Bonneil, Joel Lanoix, Dylan M. Marchione, Damien Faury, Leonie G. Mikael, Carol C.L. Chen, Wajih Jawhar, Liam D. Hendrikse, Shriya Deshmukh, Nicolas De Jay, and Sima Khazaei

Abstract

Supplementary Figures

Published
2023

7. Supplementary Data from H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone

Author

Nada Jabado, Claudia L. Kleinman, Livia Garzia, Michael D. Taylor, Stephen C. Mack, Benjamin A. Garcia, Peter W. Lewis, Pierre Thibault, Jay S. Wunder, Robert Turcotte, Brendan C. Dickson, Jason Karamchandani, Sungmi Jung, Ashot S. Harutyunyan, Véronique Lisi, Robert Eveleigh, Tianna S. Sihota, Kateryna Rossokhata, Siddhant U. Jain, Takeaki Ishii, Éric Bonneil, Joel Lanoix, Dylan M. Marchione, Damien Faury, Leonie G. Mikael, Carol C.L. Chen, Wajih Jawhar, Liam D. Hendrikse, Shriya Deshmukh, Nicolas De Jay, and Sima Khazaei

Abstract

Supplementary Information

Published
2023

8. 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

9. 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

10. 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

11. H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in Giant Cell Tumour of Bone

Author

Jay S. Wunder, Jason Karamchandani, Ashot S. Harutyunyan, Nada Jabado, Robert E. Turcotte, Tianna S. Sihota, Damien Faury, Shriya Deshmukh, Peter W. Lewis, Kateryna Rossokhata, Stephen C. Mack, Brendan C. Dickson, Livia Garzia, Pierre Thibault, Leonie G. Mikael, Liam D. Hendrikse, Dylan M. Marchione, Carol C.L. Chen, Siddhant U. Jain, Takeaki Ishii, Sima Khazaei, Nicolas De Jay, Benjamin A. Garcia, Sungmi Jung, Véronique Lisi, Michael D. Taylor, Claudia L. Kleinman, Robert Eveleigh, Wajih Jawhar, Eric Bonneil, and Joel Lanoix

Subjects
0301 basic medicine, Stromal cell, Population, Gene Expression, Bone Neoplasms, Biology, Article, Extracellular matrix, Histones, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Progenitor cell, education, Giant Cell Tumor of Bone, education.field_of_study, Tumor microenvironment, Osteoblasts, Mesenchymal stem cell, Mesenchymal Stem Cells, Osteoblast, Cell Differentiation, medicine.disease, Chromatin, Cell biology, Nucleosomes, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Mutation, Giant-cell tumor of bone
Abstract

Glycine 34-to-tryptophan (G34W) substitutions in H3.3 arise in approximately 90% of giant cell tumor of bone (GCT). Here, we show H3.3 G34W is necessary for tumor formation. By profiling the epigenome, transcriptome, and secreted proteome of patient samples and tumor-derived cells CRISPR–Cas9-edited for H3.3 G34W, we show that H3.3K36me3 loss on mutant H3.3 alters the deposition of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes redistribution of other chromatin marks and aberrant transcription, altering cell fate in mesenchymal progenitors and hindering differentiation. Single-cell transcriptomics reveals that H3.3 G34W stromal cells recapitulate a neoplastic trajectory from a SPP1+ osteoblast-like progenitor population toward an ACTA2+ myofibroblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3 G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors, which promotes neoplastic growth, pathologic recruitment of giant osteoclasts, and bone destruction. Significance: This study shows that H3.3 G34W drives GCT tumorigenesis through aberrant epigenetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interactions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT. See related commentary by Licht, p. 1794. This article is highlighted in the In This Issue feature, p. 1775

Published
2020

12. 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

13. Identification of a Novel Gammaherpesvirus in Canada lynx (Lynx canadensis)

Author

Caroline Kayko, Brian Stevens, David B. Needle, Andrew S. Lang, Marta Canuti, Ankita Kambli, Bruce Rodrigues, Liam D. Hendrikse, Jennifer Vashon, and Ryan M. Troyer

Subjects
Male, 0301 basic medicine, felid, lcsh:QR1-502, Subspecies, lcsh:Microbiology, 0403 veterinary science, Genus, glycoprotein B, Phylogeny, 0303 health sciences, Phylogenetic tree, lynx, 04 agricultural and veterinary sciences, Percavirus, 3. Good health, Infectious Diseases, Female, Identification (biology), Canada, food.ingredient, 040301 veterinary sciences, 030106 microbiology, Zoology, Lymphoproliferative disorders, cat, macromolecular substances, virus, Biology, DNA polymerase, Article, DNA sequencing, Virus, 03 medical and health sciences, Gammaherpesvirinae, food, herpesvirus, Virology, medicine, Animals, Animal species, DNA Polymerase III, 030304 developmental biology, medicine.disease, 030104 developmental biology, Novel virus, DNA, Viral, phylogenetic
Abstract

Gammaherpesviruses (GHVs) infect many animal species and are associated with lymphoproliferative disorders in some. Previously, we identified several novel GHVs in North American felids, however, a GHV had never been identified in Canada lynx (Lynx canadensis). We, therefore, hypothesized the existence of an unidentified GHV in lynx. Using degenerate nested and subsequently virus-specific PCR, we amplified and sequenced 3.4 kb of DNA from a novel GHV in lynx, which we named Lynx canadensis gammaherpesvirus 1 (LcaGHV1). Phylogenetic analysis determined that LcaGHV1 is a distinct GHV species belonging to the genus Percavirus. We then estimated the prevalence of LcaGHV1 in lynx by developing a PCR-based assay and detected LcaGHV1 DNA in 36% (95% CI: 22&ndash, 53%) of lynx spleen DNA samples from Maine, USA and 17% (95% CI: 8&ndash, 31%) from Newfoundland, Canada. The LcaGHV1 DNA sequences from Maine and Newfoundland lynx were nearly identical to each other (two nucleotide substitutions in 3.4 kb), suggesting that the unique lynx subspecies present on the island of Newfoundland (Lynx canadensis subsolanus) is infected with virus that very closely resembles virus found in mainland lynx. The potential ecologic and pathologic consequences of this novel virus for Canada lynx populations warrant further study.

Published
2019
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14. 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

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