Associação Portuguesa de Investigação em Cancro
SOX2 is a functional marker of gastric cancer stem-like cells sensitive to monensin
SOX2 is a functional marker of gastric cancer stem-like cells sensitive to monensin
Gastric cancer remains one of the most incident and deadly worldwide. It is usually detected in more advanced stages and therefore, the available treatments are not always sufficient to treat patients, leading to a low survival rate. Additionally, in some cases after an apparently successful treatment the cancer recurs. The recognition of cancer stem cells (CSCs) as keys of the tumorigenic process, metastasis and resistance to radio- and chemotherapy makes them an essential target for an efficient cancer treatment. These cells represent a small cell population in the tumor mass and have been identified through the combination of cell-surface markers. However, the use of these biomarkers may not be ideal since, within the same tumor type the cell-surface markers needed may vary. For this reason, this article, developed by researchers from the Institute of Research and Innovation in Health of the University of Porto (i3S) in collaboration with researchers from the Center for Neuroscience and Cell Biology of the University of Coimbra (CNC) and the University of Lund, shows the use of a new method to identify and study CSCs. Through the use of a reporter system based on the activity of the transcription factor SOX2, the researchers successfully identify and isolate a small population of gastric CSCs. These cells, enriched in SOX2, proved to be more proliferative, more resistant to 5-fluorouracil, capable of forming gastro-spheres under non-adherent conditions and capable of originating tumors in vivo. The subsequent performance of high-throughput screening tests to identify small molecules capable of eliminating these cells allowed the identification of the ionophore monensin as a possible agent capable of preferentially affecting the viability of the gastric CSCs. In summary, the results obtained in this work reveal that SOX2 is a relevant biomarker of gastric CSCs and expose for the first time, that monensin preferentially affects these cells, opening a possible path for the clinical test of this drug in patients with gastric cancer.
Authors and Affiliations:
1 i3S - Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal
2 IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
3 Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
4 IBMC - Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal
5 CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
6 Cell Reprogramming in Hematopoiesis and Immunity laboratory, Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84 Lund, Sweden
7 Wallenberg Center for Molecular Medicine, Lund University, 221 84 Lund, Sweden
8 Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal
9 Biology Department, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
Abstract:
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.
Journal: Cancers
