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 & 13 others Amy M. Molan, Addison M. Demer, Michelle M. Frees, Anthony E. Rizzardi, Stephen C. Schmechel, Charles G. Eberhart, Robert Brian Jenkins, Robert J. Wechsler-Reya, David J. Odde, Annie Huang, Michael D. Taylor, Aaron L. Sarver, David A. Largaespada

Research output: Contribution to journalArticle

Abstract

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 Arh-gap36, 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.

Original languageEnglish (US)
Pages (from-to)905-917
Number of pages13
JournalCancer Research
Volume79
Issue number5
DOIs
StatePublished - Mar 1 2019

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Beauty
Central Nervous System Neoplasms
Medulloblastoma
Insertional Mutagenesis
Primitive Neuroectodermal Tumors
Central Nervous System
Hedgehogs
Proto-Oncogenes
Protein Stability
Neuroblastoma
Brain Neoplasms
Mutagenesis
Carcinogenesis
Therapeutics
Gene Expression
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Beckmann, P. J., Larson, J. D., Larsson, A. T., Ostergaard, J. P., Wagner, S., Rahrmann, E. P., ... Largaespada, D. A. (2019). Sleeping beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors. Cancer Research, 79(5), 905-917. https://doi.org/10.1158/0008-5472.CAN-18-1261

Sleeping beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors. / Beckmann, Pauline J.; Larson, Jon D.; Larsson, Alex T.; Ostergaard, Jason P.; Wagner, Sandra; Rahrmann, Eric P.; Shamsan, Ghaidan A.; Otto, George M.; Williams, Rory L.; Wang, Jun; Lee, Catherine; Tschida, Barbara R.; Das, Paramita; Dubuc, Adrian M.; Moriarity, Branden S.; Picard, Daniel; Wu, Xiaochong; Rodriguez, Fausto J.; Rosemarie, Quincy; Krebs, Ryan D.; Molan, Amy M.; Demer, Addison M.; Frees, Michelle M.; Rizzardi, Anthony E.; Schmechel, Stephen C.; Eberhart, Charles G.; Jenkins, Robert Brian; Wechsler-Reya, Robert J.; Odde, David J.; Huang, Annie; Taylor, Michael D.; Sarver, Aaron L.; Largaespada, David A.

In: Cancer Research, Vol. 79, No. 5, 01.03.2019, p. 905-917.

Research output: Contribution to journalArticle

Beckmann, PJ, Larson, JD, Larsson, AT, Ostergaard, JP, Wagner, S, Rahrmann, EP, Shamsan, GA, Otto, GM, Williams, RL, Wang, J, Lee, C, Tschida, BR, Das, P, Dubuc, AM, Moriarity, BS, Picard, D, Wu, X, Rodriguez, FJ, Rosemarie, Q, Krebs, RD, Molan, AM, Demer, AM, Frees, MM, Rizzardi, AE, Schmechel, SC, Eberhart, CG, Jenkins, RB, Wechsler-Reya, RJ, Odde, DJ, Huang, A, Taylor, MD, Sarver, AL & Largaespada, DA 2019, 'Sleeping beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors', Cancer Research, vol. 79, no. 5, pp. 905-917. https://doi.org/10.1158/0008-5472.CAN-18-1261
Beckmann, Pauline J. ; Larson, Jon D. ; Larsson, Alex T. ; Ostergaard, Jason P. ; Wagner, Sandra ; Rahrmann, Eric P. ; Shamsan, Ghaidan A. ; Otto, George M. ; Williams, Rory L. ; Wang, Jun ; Lee, Catherine ; Tschida, Barbara R. ; Das, Paramita ; Dubuc, Adrian M. ; Moriarity, Branden S. ; Picard, Daniel ; Wu, Xiaochong ; Rodriguez, Fausto J. ; Rosemarie, Quincy ; Krebs, Ryan D. ; Molan, Amy M. ; Demer, Addison M. ; Frees, Michelle M. ; Rizzardi, Anthony E. ; Schmechel, Stephen C. ; Eberhart, Charles G. ; Jenkins, Robert Brian ; Wechsler-Reya, Robert J. ; Odde, David J. ; Huang, Annie ; Taylor, Michael D. ; Sarver, Aaron L. ; Largaespada, David A. / Sleeping beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors. In: Cancer Research. 2019 ; Vol. 79, No. 5. pp. 905-917.
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abstract = "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 Arh-gap36, 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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T1 - Sleeping beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors

AU - Beckmann, Pauline J.

AU - Larson, Jon D.

AU - Larsson, Alex T.

AU - Ostergaard, Jason P.

AU - Wagner, Sandra

AU - Rahrmann, Eric P.

AU - Shamsan, Ghaidan A.

AU - Otto, George M.

AU - Williams, Rory L.

AU - Wang, Jun

AU - Lee, Catherine

AU - Tschida, Barbara R.

AU - Das, Paramita

AU - Dubuc, Adrian M.

AU - Moriarity, Branden S.

AU - Picard, Daniel

AU - Wu, Xiaochong

AU - Rodriguez, Fausto J.

AU - Rosemarie, Quincy

AU - Krebs, Ryan D.

AU - Molan, Amy M.

AU - Demer, Addison M.

AU - Frees, Michelle M.

AU - Rizzardi, Anthony E.

AU - Schmechel, Stephen C.

AU - Eberhart, Charles G.

AU - Jenkins, Robert Brian

AU - Wechsler-Reya, Robert J.

AU - Odde, David J.

AU - Huang, Annie

AU - Taylor, Michael D.

AU - Sarver, Aaron L.

AU - Largaespada, David A.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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 Arh-gap36, 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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