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.

Nuclear size normally scales with the size of the cell, but in cancer this 'karyoplasmic ratio' is disrupted. This is particularly so in more metastatic tumors where changes in the karyoplasmic ratio are used in both diagnosis and prognosis for several tumor types. However, the direction of nuclear size changes differs for particular tumor types: for example in breast cancer, larger nuclear size correlates with increased metastasis, while for lung cancer smaller nuclear size correlates with increased metastasis. Thus, there must be tissue-specific drivers of the nuclear size changes, but proteins thus far linked to nuclear size regulation are widely expressed. Notably, for these tumor types, ploidy changes have been excluded as the basis for nuclear size changes, and so, the increased metastasis is more likely to have a basis in the nuclear morphology change itself. We review what is known about nuclear size regulation and postulate how such nuclear size changes can increase metastasis and why the directionality can differ for particular tumor types.

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