Chemical Interrogation of Nuclear Size Identifies Compounds with Cancer Cell Line-Specific Effects on Migration and Invasion

Background: Lower survival rates for many cancer
types correlate with changes in nuclear size/scaling in a tumor-type/tissue-specific
manner. Hypothesizing that such changes might confer an advantage
to tumor cells, we aimed at the identification of commercially available
compounds to guide further mechanistic studies. We therefore screened
for Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved
compounds that reverse the direction of characteristic tumor nuclear
size changes in PC3, HCT116, and H1299 cell lines reflecting, respectively,
prostate adenocarcinoma, colonic adenocarcinoma, and small-cell squamous
lung cancer. Results: We found distinct, largely
nonoverlapping sets of compounds that rectify nuclear size changes
for each tumor cell line. Several classes of compounds including,
e.g., serotonin uptake inhibitors, cyclo-oxygenase inhibitors, β-adrenergic
receptor agonists, and Na+/K+ ATPase inhibitors,
displayed coherent nuclear size phenotypes focused on a particular
cell line or across cell lines and treatment conditions. Several compounds
from classes far afield from current chemotherapy regimens were also
identified. Seven nuclear size-rectifying compounds selected for further
investigation all inhibited cell migration and/or invasion. Conclusions: Our study provides (a) proof of concept that
nuclear size might be a valuable target to reduce cell migration/invasion
in cancer treatment and (b) the most thorough collection of tool compounds
to date reversing nuclear size changes specific to individual cancer-type
cell lines. Although these compounds still need to be tested in primary
cancer cells, the cell line-specific nuclear size and migration/invasion
responses to particular drug classes suggest that cancer type-specific
nuclear size rectifiers may help reduce metastatic spread.

背景：众多癌症类型的生存率降低与肿瘤细胞核大小/缩放在肿瘤类型/组织特异性方式中的变化相关。假设这种变化可能赋予肿瘤细胞优势，本研究旨在识别商业可用的化合物以指导进一步的机制研究。因此，我们筛选了美国食品药品监督管理局（FDA）/欧洲药品管理局（EMA）批准的化合物，这些化合物可以逆转PC3、HCT116和H1299细胞系中特征性肿瘤细胞核大小变化的趋势，分别对应前列腺腺癌、结肠腺癌和小细胞鳞状细胞肺癌。结果：我们发现了针对每个肿瘤细胞系具有纠正核大小变化的独特、 largely nonoverlapping 的化合物集合。包括例如5-羟色胺摄取抑制剂、环氧化酶抑制剂、β-肾上腺素受体激动剂和Na+/K+ ATP酶抑制剂在内的几类化合物，均表现出针对特定细胞系或跨细胞系和治疗方案的一致核大小表型。还识别出了来自远离当前化疗方案的化合物类别。七个选定的核大小纠正化合物均被用于进一步研究，且均抑制了细胞迁移和/或侵袭。结论：本研究提供了（a）核大小可能成为降低癌症治疗中细胞迁移/侵袭的有价值靶点的概念性证据，以及（b）迄今为止关于针对特定癌症类型细胞系逆转特定核大小变化的工具化合物的最全面集合。尽管这些化合物仍需在原发癌组织中测试，但特定细胞系对特定药物类别的核大小和迁移/侵袭反应表明，针对癌症类型特定的核大小纠正剂可能有助于减少转移扩散。