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000301762 041__ $$aEnglish
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000301762 1001_ $$aTalbot, Julie$$b0
000301762 245__ $$aSonic hedgehog medulloblastomas are dependent on Netrin-1 for survival.
000301762 260__ $$a[London]$$bSpringer Nature$$c2025
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000301762 520__ $$aNetrin-1 signaling is an essential prototypical neuronal guidance mechanism during embryonic development that also regulates tumor cell survival in a variety of adult cancer entities. In line with these data, a monoclonal netrin-1 blocking antibody (anti-netrin-1 mAb/NP137) has been preclinically developed and netrin-1 blockade has recently been investigated in phase 1 and 2 clinical trials in several adult cancers. Here, we investigate the role of netrin-1 in the most common malignant pediatric brain cancer, Medulloblastoma. Interestingly, we find that netrin-1 is upregulated in medulloblastoma subgroups associated with developmental dysregulation, in particular in medulloblastoma with Sonic Hedgehog (SHH) activation. First, we demonstrate that genetic deletion of netrin-1 or systemic treatment with the clinical-stage anti-netrin-1 blocking antibody significantly reduces tumor growth in vivo in various orthotopic models of SHH medulloblastomas. Second, in vitro and in vivo, we unexpectedly uncover that SHH medulloblastomas treated with an SHH-inhibitor targeting Smoothened (SMO) increase netrin-1 expression, paving the way for combinatorial therapy. In line with that, we next show that netrin-1 blockade potentiates the efficacy of SMO inhibitor therapy in vivo. Together, our data indicate that, netrin-1 blockade, used as monotherapy or in combination with SMO inhibitors, is a promising therapeutic strategy in SHH medulloblastomas.
000301762 536__ $$0G:(DE-HGF)POF4-312$$a312 - Funktionelle und strukturelle Genomforschung (POF4-312)$$cPOF4-312$$fPOF IV$$x0
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000301762 650_7 $$0158651-98-0$$2NLM Chemicals$$aNetrin-1
000301762 650_7 $$2NLM Chemicals$$aHedgehog Proteins
000301762 650_7 $$2NLM Chemicals$$aNTN1 protein, human
000301762 650_7 $$2NLM Chemicals$$aSmoothened Receptor
000301762 650_7 $$2NLM Chemicals$$aNtn1 protein, mouse
000301762 650_7 $$2NLM Chemicals$$aTumor Suppressor Proteins
000301762 650_7 $$2NLM Chemicals$$aSHH protein, human
000301762 650_2 $$2MeSH$$aNetrin-1: metabolism
000301762 650_2 $$2MeSH$$aNetrin-1: genetics
000301762 650_2 $$2MeSH$$aNetrin-1: antagonists & inhibitors
000301762 650_2 $$2MeSH$$aMedulloblastoma: metabolism
000301762 650_2 $$2MeSH$$aMedulloblastoma: genetics
000301762 650_2 $$2MeSH$$aMedulloblastoma: pathology
000301762 650_2 $$2MeSH$$aMedulloblastoma: drug therapy
000301762 650_2 $$2MeSH$$aHedgehog Proteins: metabolism
000301762 650_2 $$2MeSH$$aHedgehog Proteins: genetics
000301762 650_2 $$2MeSH$$aAnimals
000301762 650_2 $$2MeSH$$aHumans
000301762 650_2 $$2MeSH$$aMice
000301762 650_2 $$2MeSH$$aCell Line, Tumor
000301762 650_2 $$2MeSH$$aSmoothened Receptor: antagonists & inhibitors
000301762 650_2 $$2MeSH$$aSmoothened Receptor: metabolism
000301762 650_2 $$2MeSH$$aCerebellar Neoplasms: metabolism
000301762 650_2 $$2MeSH$$aCerebellar Neoplasms: genetics
000301762 650_2 $$2MeSH$$aCerebellar Neoplasms: pathology
000301762 650_2 $$2MeSH$$aCerebellar Neoplasms: drug therapy
000301762 650_2 $$2MeSH$$aSignal Transduction
000301762 650_2 $$2MeSH$$aCell Survival: drug effects
000301762 650_2 $$2MeSH$$aTumor Suppressor Proteins: metabolism
000301762 650_2 $$2MeSH$$aTumor Suppressor Proteins: genetics
000301762 650_2 $$2MeSH$$aGene Expression Regulation, Neoplastic
000301762 650_2 $$2MeSH$$aFemale
000301762 7001_ $$aFombonne, Joanna$$b1
000301762 7001_ $$aTorrejon, Jacob$$b2
000301762 7001_ $$00000-0002-2902-8045$$aBabcock, Benjamin R$$b3
000301762 7001_ $$aMcSwain, Leon F$$b4
000301762 7001_ $$00000-0003-1614-7755$$aRama, Nicolas$$b5
000301762 7001_ $$aLospinoso Severini, Ludovica$$b6
000301762 7001_ $$aBonerandi, Emma$$b7
000301762 7001_ $$aMarsaud, Veronique$$b8
000301762 7001_ $$00000-0002-9740-2983$$aBernardi, Flavia$$b9
000301762 7001_ $$aGharsalli, Tarek$$b10
000301762 7001_ $$aGuix, Catherine$$b11
000301762 7001_ $$00000-0002-6701-0508$$aDucarouge, Benjamin$$b12
000301762 7001_ $$aNeururer, Verena$$b13
000301762 7001_ $$00000-0002-5117-2529$$aBasili, Irene$$b14
000301762 7001_ $$aMercier, Audrey L$$b15
000301762 7001_ $$00009-0001-6923-9111$$aYu, Hua$$b16
000301762 7001_ $$aForget, Antoine$$b17
000301762 7001_ $$00000-0001-8974-6551$$aIndersie, Emilie$$b18
000301762 7001_ $$00000-0001-9922-8205$$aLeboucher, Sophie$$b19
000301762 7001_ $$aSouphron, Judith$$b20
000301762 7001_ $$0P:(DE-He78)34b3639de467b2c700920d7cbc3d2110$$aOkonechnikov, Konstantin$$b21$$udkfz
000301762 7001_ $$00000-0002-4098-7482$$aWang, Wanchen$$b22
000301762 7001_ $$aKawauchi, Daisuke$$b23
000301762 7001_ $$aWainwright, Brandon J$$b24
000301762 7001_ $$aFrappaz, Didier$$b25
000301762 7001_ $$aVarlet, Pascale$$b26
000301762 7001_ $$00000-0001-5993-8077$$aDufour, Christelle$$b27
000301762 7001_ $$aBeccaria, Kevin$$b28
000301762 7001_ $$00000-0003-4076-9642$$aBlauwblomme, Thomas$$b29
000301762 7001_ $$00000-0003-1535-7515$$aMartignetti, Loredana$$b30
000301762 7001_ $$00000-0003-0274-7178$$aDi Marcotullio, Lucia$$b31
000301762 7001_ $$aPuget, Stéphanie$$b32
000301762 7001_ $$aDoz, François$$b33
000301762 7001_ $$00000-0001-9489-6781$$aBourdeaut, Franck$$b34
000301762 7001_ $$aMasliah-Planchon, Julien$$b35
000301762 7001_ $$00000-0001-7034-6400$$aGershon, Timothy R$$b36
000301762 7001_ $$00000-0003-1743-5417$$aMehlen, Patrick$$b37
000301762 7001_ $$00000-0002-7942-6674$$aAyrault, Olivier$$b38
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