Author/Authors :
Matija Snuderl، نويسنده , , Ana Batista، نويسنده , , Nathaniel D. Kirkpatrick، نويسنده , , Carmen Ruiz de Almodovar، نويسنده , , Lars Riedemann، نويسنده , , Elisa C. Walsh، نويسنده , , Rachel Anolik، نويسنده , , Yuhui Huang، نويسنده , , John D. Martin، نويسنده , , Walid Kamoun، نويسنده , , Ellen Knevels، نويسنده , , Thomas Schmidt، نويسنده , , Christian T. Farrar، نويسنده , , Benjamin J. Vakoc، نويسنده , , Nishant Mohan، نويسنده , , Euiheon Chung، نويسنده , , Sylvie Roberge، نويسنده , , Teresa Peterson، نويسنده , , Carlos Bais، نويسنده , , Boryana H. Zhelyazkova، نويسنده , , et al.، نويسنده ,
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.
