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3 results on '"Fong, Vernon"'

1. Early rhombic lip Protogenin +ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.

Author

Visvanathan A, Saulnier O, Chen C, Haldipur P, Orisme W, Delaidelli A, Shin S, Millman J, Bryant A, Abeysundara N, Wu X, Hendrikse LD, Patil V, Bashardanesh Z, Golser J, Livingston BG, Nakashima T, Funakoshi Y, Ong W, Rasnitsyn A, Aldinger KA, Richman CM, Van Ommeren R, Lee JJY, Ly M, Vladoiu MC, Kharas K, Balin P, Erickson AW, Fong V, Zhang J, Suárez RA, Wang H, Huang N, Pallota JG, Douglas T, Haapasalo J, Razavi F, Silvestri E, Sirbu O, Worme S, Kameda-Smith MM, Wu X, Daniels C, MichaelRaj AK, Bhaduri A, Schramek D, Suzuki H, Garzia L, Ahmed N, Kleinman CL, Stein LD, Dirks P, Dunham C, Jabado N, Rich JN, Li W, Sorensen PH, Wechsler-Reya RJ, Weiss WA, Millen KJ, Ellison DW, Dimitrov DS, and Taylor MD

Subjects
Humans, Animals, Mice, Rhombencephalon metabolism, Rhombencephalon embryology, Cerebellar Neoplasms metabolism, Cerebellar Neoplasms pathology, Endothelial Cells metabolism, Stem Cell Niche, Stem Cells metabolism, Coculture Techniques, Embryonic Structures, Metencephalon embryology, Medulloblastoma pathology, Medulloblastoma metabolism, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology
Abstract

We identify a population of Protogenin-positive (PRTG +ve ) MYC high NESTIN low stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RL VZ ). Oncogenic transformation of early Prtg +ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG +ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RL VZ , a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTG high compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RL VZ PRTG +ve stem cells inhabiting a specific perivascular niche. Targeting the PRTG high compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB., Competing Interests: Declaration of interests The authors declare no competing interests. A patent related to this work was submitted by University of Pittsburgh (University Docket No. 05700/F&R ref. 48881-0028P01), US 63/275,326, “Molecules that bind to Protogenin polypeptides.”, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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2. The transcriptional landscape of Shh medulloblastoma.

Author

Skowron P, Farooq H, Cavalli FMG, Morrissy AS, Ly M, Hendrikse LD, Wang EY, Djambazian H, Zhu H, Mungall KL, Trinh QM, Zheng T, Dai S, Stucklin ASG, Vladoiu MC, Fong V, Holgado BL, Nor C, Wu X, Abd-Rabbo D, Bérubé P, Wang YC, Luu B, Suarez RA, Rastan A, Gillmor AH, Lee JJY, Zhang XY, Daniels C, Dirks P, Malkin D, Bouffet E, Tabori U, Loukides J, Doz FP, Bourdeaut F, Delattre OO, Masliah-Planchon J, Ayrault O, Kim SK, Meyronet D, Grajkowska WA, Carlotti CG, de Torres C, Mora J, Eberhart CG, Van Meir EG, Kumabe T, French PJ, Kros JM, Jabado N, Lach B, Pollack IF, Hamilton RL, Rao AAN, Giannini C, Olson JM, Bognár L, Klekner A, Zitterbart K, Phillips JJ, Thompson RC, Cooper MK, Rubin JB, Liau LM, Garami M, Hauser P, Li KKW, Ng HK, Poon WS, Yancey Gillespie G, Chan JA, Jung S, McLendon RE, Thompson EM, Zagzag D, Vibhakar R, Ra YS, Garre ML, Schüller U, Shofuda T, Faria CC, López-Aguilar E, Zadeh G, Hui CC, Ramaswamy V, Bailey SD, Jones SJ, Mungall AJ, Moore RA, Calarco JA, Stein LD, Bader GD, Reimand J, Ragoussis J, Weiss WA, Marra MA, Suzuki H, and Taylor MD

Subjects
Adolescent, Adult, Child, Child, Preschool, Female, Gene Regulatory Networks, Genetic Variation, Humans, Infant, Male, Middle Aged, Signal Transduction genetics, Young Adult, Cerebellar Neoplasms genetics, Gene Expression Regulation, Neoplastic, Hedgehog Proteins genetics, Medulloblastoma genetics, Transcriptome
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.

Published
2021
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3. 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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