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A novel program of infiltrative control in astrocytomas: ADAM23 depletion promotes cell invasion by activating γ-secretase complex

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Jandrey, Elisa Helena Farias ; Barnabe, Gabriela Filoso ; Maldaun, Marcos ; Asprino, Paula Fontes ; dos Santos, Natalia Cristina ; Inoue, Lilian Tiemi ; Rozanski, Andrei ; Galante, Pedro Alexandre Favoretto ; Marie, Suely Kazue Nagahashi ; Oba-Shinjo, Sueli Mieko ; dos Santos, Tiago Goss ; Chammas, Roger ; Lancellotti, Carmen Lucia Penteado ; Furnari, Frank B. ; Camargo, Anamaria Aranha ; Costa, Erico Tosoni
Número total de Autores: 16
Tipo de documento: Artigo Científico
Fonte: NEURO-ONCOLOGY ADVANCES; v. 5, n. 1, p. 13-pg., 2023-11-27.
Resumo

Background. Infiltration is a life-threatening growth pattern in malignant astrocytomas and a significant cause of therapy resistance. It results in the tumor cell spreading deeply into the surrounding brain tissue, fostering tumor recurrence and making complete surgical resection impossible. We need to thoroughly understand the mechanisms underlying diffuse infiltration to develop effective therapies.Methods We integrated in vitro and in vivo functional assays, RNA sequencing, clinical, and expression information from public data sets to investigate the role of ADAM23 expression coupling astrocytoma's growth and motility.Results. ADAM23 downregulation resulted in increased infiltration, reduced tumor growth, and improved overall survival in astrocytomas. Additionally, we show that ADAM23 deficiency induces gamma-secretase (GS) complex activity, contributing to the production and deposition of the Amyloid-beta and release of NICD. Finally, GS ablation in ADAM23-low astrocytomas induced a significant inhibitory effect on the invasive programs.Conclusions. Our findings reveal a role for ADAM23 in regulating the balance between cell proliferation and invasiveness in astrocytoma cells, proposing GS inhibition as a therapeutic option in ADAM23 low-expressing astrocytomas. (AU)

Processo FAPESP: 17/13622-0 - Estudo das estruturas secundárias em astrocitomas: análise quantitativa do crescimento infiltrativo e sua correlação com os níveis de expressão do gene ADAM23 em modelos animais.
Beneficiário:Natália Cristina dos Santos
Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
Processo FAPESP: 16/06857-9 - Sinalização de ADAM23 em glioblastomas e seu papel no controle da via de Wnt
Beneficiário:Elisa Helena Farias Jandrey
Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
Processo FAPESP: 16/07463-4 - Caracterização molecular e estudo do papel funcional do gene adam23 na progressão de gliomas difusos.
Beneficiário:Erico Tosoni Costa
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 14/04945-2 - Relevância de ADAM23 na modulação da via de Wnt na progressão de gliomas
Beneficiário:Gabriela Filoso Barnabé
Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado