Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma

Matija Snuderl; Ana Batista; Nathaniel D. Kirkpatrick; Carmen Ruiz De Almodovar; Lars Riedemann; Elisa C. Walsh; Rachel Anolik; Yuhui Huang; John D. Martin; Walid Kamoun; Ellen Knevels; Thomas Schmidt; Christian T. Farrar; Benjamin J. Vakoc; Nishant Mohan; Euiheon Chung; Sylvie Roberge; Teresa Peterson; Carlos Bais; Boryana H. Zhelyazkova; Stephen Yip; Martin Hasselblatt; Claudia Rossig; Elisabeth Niemeyer; Napoleone Ferrara; Michael Klagsbrun; Dan G. Duda; Dai Fukumura; Lei Xu; Peter Carmeliet; Rakesh K. Jain

doi:10.1016/j.cell.2013.01.036

Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma

Matija Snuderl, Ana Batista, Nathaniel D. Kirkpatrick, Carmen Ruiz De Almodovar, Lars Riedemann, Elisa C. Walsh, Rachel Anolik, Yuhui Huang, John D. Martin, Walid Kamoun, Ellen Knevels, Thomas Schmidt, Christian T. Farrar, Benjamin J. Vakoc, Nishant Mohan, Euiheon Chung, Sylvie Roberge, Teresa Peterson, Carlos Bais, Boryana H. ZhelyazkovaStephen Yip, Martin Hasselblatt, Claudia Rossig, Elisabeth Niemeyer, Napoleone Ferrara, Michael Klagsbrun, Dan G. Duda, Dai Fukumura, Lei Xu, Peter Carmeliet, Rakesh K. Jain

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Abstract

Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and are associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas, independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastasis, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1-and not vascular endothelial growth factor receptor 1-to promote tumor cell survival. This critical tumor-stroma interaction- mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes-supports the development of therapies targeting PlGF/Nrp1 pathway.

Original language	English (US)
Pages (from-to)	1065-1076
Number of pages	12
Journal	Cell
Volume	152
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2013.01.036
State	Published - Feb 28 2013

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Snuderl, M., Batista, A., Kirkpatrick, N. D., De Almodovar, C. R., Riedemann, L., Walsh, E. C., Anolik, R., Huang, Y., Martin, J. D., Kamoun, W., Knevels, E., Schmidt, T., Farrar, C. T., Vakoc, B. J., Mohan, N., Chung, E., Roberge, S., Peterson, T., Bais, C., ... Jain, R. K. (2013). Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell, 152(5), 1065-1076. https://doi.org/10.1016/j.cell.2013.01.036

Snuderl, M, Batista, A, Kirkpatrick, ND, De Almodovar, CR, Riedemann, L, Walsh, EC, Anolik, R, Huang, Y, Martin, JD, Kamoun, W, Knevels, E, Schmidt, T, Farrar, CT, Vakoc, BJ, Mohan, N, Chung, E, Roberge, S, Peterson, T, Bais, C, Zhelyazkova, BH, Yip, S, Hasselblatt, M, Rossig, C, Niemeyer, E, Ferrara, N, Klagsbrun, M, Duda, DG, Fukumura, D, Xu, L, Carmeliet, P & Jain, RK 2013, 'Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma', Cell, vol. 152, no. 5, pp. 1065-1076. https://doi.org/10.1016/j.cell.2013.01.036

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title = "Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma",

abstract = "Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and are associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas, independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastasis, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1-and not vascular endothelial growth factor receptor 1-to promote tumor cell survival. This critical tumor-stroma interaction- mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes-supports the development of therapies targeting PlGF/Nrp1 pathway.",

author = "Matija Snuderl and Ana Batista and Kirkpatrick, \{Nathaniel D.\} and \{De Almodovar\}, \{Carmen Ruiz\} and Lars Riedemann and Walsh, \{Elisa C.\} and Rachel Anolik and Yuhui Huang and Martin, \{John D.\} and Walid Kamoun and Ellen Knevels and Thomas Schmidt and Farrar, \{Christian T.\} and Vakoc, \{Benjamin J.\} and Nishant Mohan and Euiheon Chung and Sylvie Roberge and Teresa Peterson and Carlos Bais and Zhelyazkova, \{Boryana H.\} and Stephen Yip and Martin Hasselblatt and Claudia Rossig and Elisabeth Niemeyer and Napoleone Ferrara and Michael Klagsbrun and Duda, \{Dan G.\} and Dai Fukumura and Lei Xu and Peter Carmeliet and Jain, \{Rakesh K.\}",

year = "2013",

month = feb,

day = "28",

doi = "10.1016/j.cell.2013.01.036",

language = "English (US)",

volume = "152",

pages = "1065--1076",

journal = "Cell",

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T1 - Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma

AU - Snuderl, Matija

AU - Batista, Ana

AU - Kirkpatrick, Nathaniel D.

AU - De Almodovar, Carmen Ruiz

AU - Riedemann, Lars

AU - Walsh, Elisa C.

AU - Anolik, Rachel

AU - Huang, Yuhui

AU - Martin, John D.

AU - Kamoun, Walid

AU - Knevels, Ellen

AU - Schmidt, Thomas

AU - Farrar, Christian T.

AU - Vakoc, Benjamin J.

AU - Mohan, Nishant

AU - Chung, Euiheon

AU - Roberge, Sylvie

AU - Peterson, Teresa

AU - Bais, Carlos

AU - Zhelyazkova, Boryana H.

AU - Yip, Stephen

AU - Hasselblatt, Martin

AU - Rossig, Claudia

AU - Niemeyer, Elisabeth

AU - Ferrara, Napoleone

AU - Klagsbrun, Michael

AU - Duda, Dan G.

AU - Fukumura, Dai

AU - Xu, Lei

AU - Carmeliet, Peter

AU - Jain, Rakesh K.

PY - 2013/2/28

Y1 - 2013/2/28

N2 - Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and are associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas, independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastasis, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1-and not vascular endothelial growth factor receptor 1-to promote tumor cell survival. This critical tumor-stroma interaction- mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes-supports the development of therapies targeting PlGF/Nrp1 pathway.

AB - Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and are associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas, independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastasis, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1-and not vascular endothelial growth factor receptor 1-to promote tumor cell survival. This critical tumor-stroma interaction- mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes-supports the development of therapies targeting PlGF/Nrp1 pathway.

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SN - 0092-8674

VL - 152

SP - 1065

EP - 1076

JO - Cell

JF - Cell

IS - 5

ER -

Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma

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