Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA.
Cells. 2021 Oct 16;10(10):2771. doi: 10.3390/cells10102771.
Cancer stem cells, in contrast to their more differentiated daughter cells, can endure genotoxic insults, escape apoptosis, and cause tumor recurrence. Understanding how normal adult stem cells survive and go to quiescence may help identify druggable pathways that cancer stem cells have co-opted. In this study, we utilize a genetically tractable model for stem cell survival in the gonad to screen drug candidates and probe chemical-genetic interactions. Our study employs three levels of small molecule screening: (1) a medium-throughput primary screen in male germline stem cells (GSCs), (2) a secondary screen with irradiation and protein-constrained food in female GSCs, and (3) a tertiary screen in breast cancer organoids in vitro. Herein, we uncover a series of small molecule drug candidates that may sensitize cancer stem cells to apoptosis. Further, we have assessed these small molecules for chemical-genetic interactions in the germline and identified the NF-κB pathway as an essential and druggable pathway in GSC quiescence and viability. Our study demonstrates the power of the stem cell niche as a model system for targeted drug discovery.
与分化程度更高的子细胞相比，癌症干细胞能够耐受遗传毒性损伤、逃避细胞凋亡，并导致肿瘤复发。了解正常成体干细胞如何存活并进入静止状态，可能有助于确定癌症干细胞共同采用的可药物干预的途径。在这项研究中，我们利用一种可遗传操控的 生殖细胞中干细胞存活模型，进行药物候选物的筛选，并探究化学遗传学相互作用。我们的研究采用了三个层次的小分子筛选：（1）在雄性生殖干细胞（GSCs）中进行中等通量的初级筛选，（2）在雌性 GSCs 中进行辐照和蛋白限制食物的二级筛选，以及（3）在乳腺癌类器官中的三级筛选。在此，我们发现了一系列可能使癌症干细胞更容易发生细胞凋亡的小分子药物候选物。此外，我们还评估了这些小分子在生殖系中的化学遗传相互作用，并确定 NF-κB 途径是 GSC 静止和存活的必需和可药物干预途径。我们的研究证明了 生殖细胞龛作为靶向药物发现的模型系统的强大功能。
