Novo oncogene com valor prognóstico identificado em glioblastoma

Investigadores do Instituto de Investigação em Ciências da Vida e da Saúde (ICVS), Escola de Medicina, Universidade do Minho, identificaram uma proteína denominada WNT6 como um novo biomarcador de prognóstico em glioblastoma (GBM), o tumor cerebral primário mais maligno e frequente em adultos, causando uma sobrevivência mediana de apenas 15 meses após o diagnóstico. Este trabalho demonstrou que o WNT6 está sobre-expresso em GBM, promovendo aumentos da viabilidade celular, proliferação, invasão, migração, capacidade de células estaminais de GBM e resistência à quimioterapia, estabelecendo o WNT6 como um novo fator oncogénico em glioma. Com recurso a modelos in vivo de GBM intracraniais em ratinho, e usando modelos celulares com diferentes níveis de expressão de WNT6, a equipa demonstrou que o WNT6 promove diversas características de agressividade tumoral, e associa-se a uma menor sobrevida dos ratinhos. A nível mecanístico, identificaram-se as vias de sinalização WNT/β-catenina, SFK e STAT3 como potenciais mecanismos de sinalização mediados pelo WNT6 em GBM. Estas associações foram corroboradas em pacientes com GBM, demonstrando também que o WNT6 é um biomarcador de prognóstico associado a uma menor sobrevida dos pacientes em diversas coortes. Estes resultados poderão ter um impacto crucial na estratificação dos pacientes com GBM, bem como no desenvolvimento de novas opções terapêuticas mais eficazes para estes doentes.

Autores e Afiliações:

Gonçalves CS^1,2, Vieira de Castro J^1,2, Pojo M^1,2, Martins EP^1,2, Queirós S^1,2, Chautard E^3,4, Taipa R⁵, Pires MM⁵, Pinto AA⁶, Pardal F⁷, Custódia C⁸, Faria CC^8,9, Clara C¹⁰, Reis RM^1,2,10, Sousa N^1,2, Costa BM^1,2.

¹ Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal.

² ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.

³ Université Clermont Auvergne, INSERM, U1240 IMoST, 63000 Clermont Ferrand, France.

⁴ Pathology Department, Université Clermont Auvergne, Centre Jean Perrin, 63011 Clermont-Ferrand, France.

⁵ Neuropathology Unit, Department of Neurosciences, Centro Hospitalar do Porto, Porto, Portugal.

⁶ Department of Neurosurgery, Hospital Escala Braga, Sete Fontes - São Victor 4710-243 Braga, Portugal.

⁷ Department of Pathology, Hospital Escala Braga, Sete Fontes - São Victor 4710-243 Braga, Portugal.

⁸ Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

⁹ Neurosurgery Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte (CHLN), Lisbon, Portugal.

¹⁰ Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos - S. Paulo, Brazil.

Abstract:

Glioblastoma (GBM) is a universally fatal brain cancer, for which novel therapies targeting specific underlying oncogenic events are urgently needed. While the WNT pathway has been shown to be frequently activated in GBM, constituting a potential therapeutic target, the relevance of WNT6, an activator of this pathway, remains unknown. Methods: WNT6 protein and mRNA levels were evaluated in GBM. WNT6 levels were silenced or overexpressed in GBM cells to assess functional effects in vitro and in vivo. Phospho-kinase arrays and TCF/LEF reporter assays were used to identify WNT6-signaling pathways, and significant associations with stem cell features and cancer-related pathways were validated in patients. Survival analyses were performed with Cox regression and Log-rank tests. Meta-analyses were used to calculate the estimated pooled effect. Results: We show that WNT6 is significantly overexpressed in GBMs, as compared to lower-grade gliomas and normal brain, at mRNA and protein levels. Functionally, WNT6 increases typical oncogenic activities in GBM cells, including viability, proliferation, glioma stem cell capacity, invasion, migration, and resistance to temozolomide chemotherapy. Concordantly, in in vivo orthotopic GBM mice models, using both overexpressing and silencing models, WNT6 expression was associated with shorter overall survival, and increased features of tumor aggressiveness. Mechanistically, WNT6 contributes to activate typical oncogenic pathways, including Src and STAT, which intertwined with the WNT pathway may be critical effectors of WNT6-associated aggressiveness in GBM. Clinically, we establish WNT6 as an independent prognostic biomarker of shorter survival in GBM patients from several independent cohorts. Conclusion: Our findings establish WNT6 as a novel oncogene in GBM, opening opportunities to develop more rational therapies to treat this highly aggressive tumor.

Revista: Theranostics. 2018 Sep 9;8(17):4805-4823. doi: 10.7150/thno.25025. eCollection 2018.

Link: http://www.thno.org/v08p4805.htm