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Targeting nuclear size: a new approach to reduce metastasis?

A screen study reveals that drugs reverting nuclear size changes in metastatic tumour cells also reduce the cell's increased ability to migrate.

For over 150 years, scientists have used changes in nuclear size prognostically, because such changes strongly correlate with increased metastasis for many cancer types.  Mechanisms underlying this are still not well understood, especially as the nuclear size changes can be in both directions: for instance, size increases in prostate and breast cancer, and decreases in lung cancer both correlate with increased metastasis.

Researchers at the Universities of Edinburgh, Montreal, Cornell and Eastern Finland worked together to screen for drugs that reversed nuclear size changes in cells from 3 metastatic cancer types. They found that different sets of drugs were effective in this purpose for each cancer type.

Many drugs for other indications could be repurposed for cancer treatment

What drives metastasis is still the subject of considerable research. When cancers metastasize, the cells become more migratory and this enables them to spread the cancer through the body. Misregulation of nuclear size could contribute to this process in that a smaller nucleus might make it easier for the cell to squeeze through junctions to enter other tissues, while a bigger nucleus might be more malleable to enable such squeezing. Because the nucleus connects to the cytoskeleton, changing nuclear size would also affect the balance of these connections and thus affect the speed of cell migration.

Accordingly, for nearly all drugs tested in detail in this study, correcting metastasis-associated nuclear size changes reduced cell migration and invasion. Beyond those drugs tested in detail, the screen identified many drug classes not previously used to treat cancer with cell-type specific corrective effects on nuclear size. These include drugs for depression, killing parasitic worms, and many others.

As these drugs acted cancer cell-type specifically in the study and they are already known to be non-toxic to people, they could potentially be helpful in reducing metastasis without increasing the already high toxicity of chemotherapy regimens. Since only FDA/EMA-approved drugs were tested in this study, they could be delivered much more quickly to clinic. While each of these potential drugs should be tested in detail before actual use in treating cancer patients, this screen identified distinct sets of a dozen drugs that may prove effective for each of three cancers.

“Engaging similar screens for other cancer types using nuclear size as a simple, easy-to-access readout will likely identify many more cancer-type specific drugs with potential to reduce metastasis with limited systemic toxicity”, says Senior Researcher Sylvain Tollis, leader of the Quantitative Cell Biology group at the Institute of Biomedicine, University of Eastern Finland.

“Hence, we hope that this proof-of-concept study will stimulate more research in this direction,” adds Docent Leena Latonen who leads the Cancer Stress Biology group at UEF.

The study, published in ACS Chemical Biology, was funded principally by the Wellcome Trust, Medical Research Council UK, National Institutes of Health USA, European Research Council, Canadian Institutes of Health Research, Sigrid Jusélius Foundation, and the Cancer Society of Finland.

Research article:

Sylvain Tollis, Andrea Rizzotto, Nhan T. Pham, Sonja Koivukoski, Aishwarya Sivakumar, Steven Shave, Jan Wildenhain, Nikolaj Zuleger, Jeremy T. Keys, Jayne Culley, Yijing Zheng, Jan Lammerding, Neil O. Carragher, Valerie G. Brunton, Leena Latonen, Manfred Auer, Mike Tyers, and Eric C. Schirmer. Chemical Interrogation of Nuclear Size Identifies Compounds with Cancer Cell Line-Specific Effects on Migration and Invasion. ACS Chem. Biol. 2022, published online 24 February 2022.