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Sleeping Beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors

Beckmann, Pauline J. and Williams, Rory L. (2019) Sleeping Beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors. Cancer Research, 79 (5). pp. 905-917. ISSN 0008-5472.

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Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. Significance: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.

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Williams, Rory L.0000-0001-7754-4207
Alternate Title:SB identifies novel drivers in medulloblastoma and CNS-PNET
Additional Information:© 2019 American Association for Cancer Research. Received April 25, 2018. Revision received November 7, 2018. Accepted December 31, 2018. Published Online First January 23, 2019. Disclosure of Potential Conflicts of Interest: D.A. Largaespada is chairman of scientific advisory board at B-MoGen, chief scientific officer at Surrogen, reports receiving commercial research grant from Genentech, and has ownership interest (including stock, patents, etc.) in Surrogen, ImmuSoft, NeoClone, and B-MoGen. No potential conflicts of interest were disclosed by the other authors. Authors' Contributions: Conception and design: P.J. Beckmann, J.D. Larson, E.P. Rahrmann, P. Das, R.J. Wechsler-Reya, D.J. Odde, A.L. Sarver, D.A. Largaespada. Development of methodology: P.J. Beckmann, J.D. Larson, R.L. Williams, B.R. Tschida, P. Das, R.D. Krebs, M.M. Frees, A.E. Rizzardi, S.C. Schmechel, A.L. Sarver, D.A. Largaespada. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): P.J. Beckmann, J.D. Larson, A.T. Larsson, J.P. Ostergaard, S. Wagner, E.P. Rahrmann, G.A. Shamsan, G.M. Otto, R.L. Williams, J. Wang, C. Lee, P. Das, B.S. Moriarity, X. Wu, Q. Rosemarie, R.D. Krebs, A.M. Molan, A.M. Demer, M.M. Frees, A.E. Rizzardi, S.C. Schmechel, C.G. Eberhart, R.B. Jenkins, R.J. Wechsler-Reya. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): P.J. Beckmann, J.D. Larson, A.T. Larsson, J.P. Ostergaard, E.P. Rahrmann, G.A. Shamsan, J. Wang, C. Lee, A.M. Dubuc, D. Picard, F.J. Rodriguez, R.D. Krebs, S.C. Schmechel, R.B. Jenkins, R.J. Wechsler-Reya, D.J. Odde, A. Huang, M.D. Taylor, A.L. Sarver. Writing, review, and/or revision of the manuscript: P.J. Beckmann, J.D. Larson, A.T. Larsson, J.P. Ostergaard, G.A. Shamsan, J. Wang, C. Lee, B.R. Tschida, A.M. Dubuc, B.S. Moriarity, D. Picard, F.J. Rodriguez, Q. Rosemarie, R.D. Krebs, A.M. Molan, A.M. Demer, S.C. Schmechel, C.G. Eberhart, R.B. Jenkins, D.J. Odde, M.D. Taylor, A.L. Sarver, D.A. Largaespada. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): P.J. Beckmann, J.D. Larson, A.T. Larsson, J.P. Ostergaard, A.E. Rizzardi, A.L. Sarver. Study supervision: P.J. Beckmann, J.D. Larson, R.J. Wechsler-Reya, D.J. Odde, D.A. Largaespada. Other (cell Culture and other assays performed in the study): R.D. Krebs. This work was supported by UofMN Genomics Center, UofMN Biology Materials Procurements Network, Research Animal Resources, and University Imaging Centers that are supported by the NCI. Support for this research was provided by The American Cancer Society (Research Professor Award no. 123939 to D.A. Largaespada), the NIH (U54CA210190 to D.A. Largaespada and D.J. Odde; R01CA113636 to D.A. Largaespada; T32 T32GM113846 to P.J. Beckmann; R50-CA211249 to A.L. Sarver; T32 AI083196 to B.R. Tschida; T32CA009138 to J.D. Larson; and R01CA172986 to D.J. Odde), the Children's Cancer Research Fund, and the Hedberg Family Chair (all to D.A. Largaespada). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding AgencyGrant Number
American Cancer Society123939
NIH Predoctoral FellowshipT32 GM113846
NIH Predoctoral FellowshipT32 AI083196
NIH Predoctoral FellowshipT32 CA009138
Children's Cancer Research FundUNSPECIFIED
Hedberg Family ChairUNSPECIFIED
University of MinnesotaUNSPECIFIED
National Cancer InstituteUNSPECIFIED
Subject Keywords:SB, Medulloblastoma, CNS-PNET, Arhgap36, Foxr2
Issue or Number:5
Record Number:CaltechAUTHORS:20190128-145012448
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Official Citation:Sleeping Beauty Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors. Pauline J. Beckmann, Jon D. Larson, Alex T. Larsson, Jason P. Ostergaard, Sandra Wagner, Eric P. Rahrmann, Ghaidan A. Shamsan, George M. Otto, Rory L. Williams, Jun Wang, Catherine Lee, Barbara R. Tschida, Paramita Das, Adrian M. Dubuc, Branden S. Moriarity, Daniel Picard, Xiaochong Wu, Fausto J. Rodriguez, Quincy Rosemarie, Ryan D. Krebs, Amy M. Molan, Addison M. Demer, Michelle M. Frees, Anthony E. Rizzardi, Stephen C.Schmechel, Charles G. Eberhart, Robert B. Jenkins, Robert J. Wechsler-Reya, David J.Odde, Annie Huang, Michael D. Taylor, Aaron L. Sarver and David A. Largaespada. Cancer Res March 1 2019 (79) (5) 905-917; DOI: 10.1158/0008-5472.CAN-18-1261
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:92499
Deposited By: Tony Diaz
Deposited On:29 Jan 2019 16:12
Last Modified:09 Mar 2020 13:19

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