Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany.
Biotechnology Center (BIOTEC), Technische Universität Dresden, Dresden, Germany.
FASEB J. 2019 Aug;33(8):9235-9249. doi: 10.1096/fj.201802603RR. Epub 2019 May 30.
Cancer cells can switch between signaling pathways to regulate growth under different conditions. In the tumor microenvironment, this likely helps them evade therapies that target specific pathways. We must identify all possible states and utilize them in drug screening programs. One such state is characterized by expression of the transcription factor Hairy and Enhancer of Split 3 () and sensitivity to knockdown, and it can be modeled . Here, we cultured 3 primary human brain cancer cell lines under 3 different culture conditions that maintain low, medium, and high expression and characterized gene regulation and mechanical phenotype in these states. We assessed gene expression regulation following knockdown in the -high conditions. We then employed a commonly used human brain tumor cell line to screen Food and Drug Administration (FDA)-approved compounds that specifically target the -high state. We report that cells from multiple patients behave similarly when placed under distinct culture conditions. We identified 37 FDA-approved compounds that specifically kill cancer cells in the high--expression conditions. Our work reveals a novel signaling state in cancer, biomarkers, a strategy to identify treatments against it, and a set of putative drugs for potential repurposing.-Poser, S. W., Otto, O., Arps-Forker, C., Ge, Y., Herbig, M., Andree, C., Gruetzmann, K., Adasme, M. F., Stodolak, S., Nikolakopoulou, P., Park, D. M., Mcintyre, A., Lesche, M., Dahl, A., Lennig, P., Bornstein, S. R., Schroeck, E., Klink, B., Leker, R. R., Bickle, M., Chrousos, G. P., Schroeder, M., Cannistraci, C. V., Guck, J., Androutsellis-Theotokis, A. Controlling distinct signaling states in cultured cancer cells provides a new platform for drug discovery.
癌细胞可以在不同的条件下通过信号通路转换来调节生长。在肿瘤微环境中，这可能有助于它们逃避针对特定通路的治疗。我们必须确定所有可能的状态，并将其应用于药物筛选计划中。有一种状态的特征是转录因子 hairy 和 Enhancer of Split 3 () 的表达以及对 knockdown 的敏感性，并且可以通过建模来模拟。在这里，我们在 3 种不同的培养条件下培养了 3 种原代人脑癌细胞系，这些条件维持低、中、高表达，并在这些状态下对基因调控和机械表型进行了表征。我们评估了在 -high 条件下 knockdown 后的基因表达调控。然后，我们使用一种常用的人脑肿瘤细胞系筛选食品和药物管理局 (FDA) 批准的化合物，这些化合物专门针对 -high 状态。我们报告说，在不同的培养条件下，来自多个患者的细胞表现相似。我们鉴定出 37 种 FDA 批准的化合物，这些化合物专门在高表达条件下杀死癌细胞。我们的工作揭示了癌症中的一种新的信号状态、生物标志物、一种识别针对它的治疗方法的策略以及一组潜在的潜在再利用药物。-Poser, S. W., Otto, O., Arps-Forker, C., Ge, Y., Herbig, M., Andree, C., Gruetzmann, K., Adasme, M. F., Stodolak, S., Nikolakopoulou, P., Park, D. M., Mcintyre, A., Lesche, M., Dahl, A., Lennig, P., Bornstein, S. R., Schroeck, E., Klink, B., Leker, R. R., Bickle, M., Chrousos, G. P., Schroeder, M., Cannistraci, C. V., Guck, J., Androutsellis-Theotokis, A. 在培养的癌细胞中控制不同的信号状态为药物发现提供了一个新的平台。
