A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin

• Autor(a) principal: Pádua, Diana
• Data de Publicação: 2020
• Outros Autores: Barros, Rita, Amaral, Ana Luísa, Mesquita, Patrícia, Freire, Ana Filipa, Sousa, Mafalda, Maia, André Filipe, Caiado, Inês, Fernandes, Hugo, Pombinho, António, Pereira, Carlos Filipe, Almeida, Raquel
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/105848; https://doi.org/10.3390/cancers12020495
• topic: cancer stem cells; gastric cancer; SOX2; monensin; SORE6-GFP reporter system; drug resistance; high-throughput screening

Gastric cancer remains a serious health burden with few therapeutic options. Therefore, the recognition of cancer stem cells (CSCs) as seeds of the tumorigenic process makes them a prime therapeutic target. Knowing that the transcription factors SOX2 and OCT4 promote stemness, our approach was to isolate stem-like cells in human gastric cancer cell lines using a traceable reporter system based on SOX2/OCT4 activity (SORE6-GFP). Cells transduced with the SORE6-GFP reporter system were sorted into SORE6+ and SORE6- cell populations, and their biological behavior characterized. SORE6+ cells were enriched for SOX2 and exhibited CSC features, including a greater ability to proliferate and form gastrospheres in non-adherent conditions, a larger in vivo tumor initiating capability, and increased resistance to 5-fluorouracil (5-FU) treatment. The overexpression and knockdown of SOX2 revealed a crucial role of SOX2 in cell proliferation and drug resistance. By combining the reporter system with a high-throughput screening of pharmacologically active small molecules we identified monensin, an ionophore antibiotic, displaying selective toxicity to SORE6+ cells. The ability of SORE6-GFP reporter system to recognize cancer stem-like cells facilitates our understanding of gastric CSC biology and serves as a platform for the identification of powerful therapeutics for targeting gastric CSCs.