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Inhibition of PlexA1-mediated brain tumor growth and tumor-associated angiogenesis using a transmembrane domain targeting peptide

2016; Impact Journals LLC; Volume: 7; Issue: 36 Linguagem: Inglês

10.18632/oncotarget.11072

1949-2553

Laurent Jacob, Paul Sawma, Norbert Garnier, Lionel Meyer, Justine Fritz, Thomas Hussenet, Caroline Spenlé, Jacky G. Goetz, Julien Vermot, Aurore Fernandez, Nadège Baumlin, Samia Aci‐Sèche, Gertraud Orend, G. Roussel, Gérard Crémel, Monique Genest, P. Hubert, Dominique Bagnard,

Hippo pathway signaling and YAP/TAZ

The neuropilin-plexin receptor complex regulates tumor cell migration and proliferation and thus is an interesting therapeutic target. High expression of neuropilin-1 is indeed associated with a bad prognosis in glioma patients. Q-RTPCR and tissue-array analyses showed here that Plexin-A1 is highly expressed in glioblastoma and that the highest level of expression correlates with the worse survival of patients. We next identified a developmental and tumor-associated pro-angiogenic role of Plexin-A1. Hence, by using molecular simulations and a two-hybrid like assay in parallel with biochemical and cellular assays we developed a specific Plexin-A1 peptidic antagonist disrupting transmembrane domain-mediated oligomerization of the receptor and subsequent signaling and functional activity. We found that this peptide exhibits anti-tumor activity in vivo on different human glioblastoma models including glioma cancer stem cells. Thus, screening Plexin-A1 expression and targeting Plexin-A1 in glioblastoma patients exhibit diagnostic and therapeutic value.