The shape of the cell nucleus influences the success of cancer treatment

Photo Credit: Thor Balkhed

Cancer cells with a cell nucleus that is easily deformed are more sensitive to drugs that damage DNA. These are the findings of a new study by researchers at Linköping University. The results may also explain why combining certain cancer drugs can produce the opposite of the intended effect. The study has been published in the journal Nature Communications. 

A few years ago, a new type of drug was introduced that exploits deficiencies in cancer cells’ ability to repair damage to their DNA. These drugs, called PARP1 inhibitors, are used against cancers that have mutations in genes involved in DNA repair, such as the breast cancer gene 1 (BRCA1). This gene has such a central role in the cell’s ability to repair serious DNA damage that mutations in it greatly increase the risk of developing cancer, often at a young age. The risk is so high that some women with a mutated BRCA1 gene choose to have their breasts and ovaries surgically removed to prevent cancer. 

Francisca Lottersberger, associate professor.
Photo Credit: Thor Balkhed

PARP1 inhibitors are used in healthcare to treat certain types of familiar breast, ovary, pancreas, and prostate cancers. However, some tumor cells develop resistance to PARP inhibitors. Especially late-stage cancers, that have spread throughout the body, are more resistant to this treatment. Understanding how this resistance develops, and possibly prevents it, is therefore of great interest. 

The researchers behind the current study suspected that the deformability of the cell nucleus could be an important factor in the development of resistance to treatment. Scientists discovered about 150 years ago that cancer cells have abnormally shaped nuclei. This is one of the first signs of cancer. But does it have any practical significance? 

“We now show that the cell nucleus deforms as one of the reactions to DNA damage. We also see that cancer cells with a deformed cell nucleus are more damaged by treatment with PARP inhibitors. This raises the question: can molecules that make the cell nucleus more deformable be used clinically to increase the effect of treatment?” says Francisca Lottersberger, associate professor at Linköping University, who led the study. 

The researchers demonstrate that changes in the shape of the nucleus are an active process controlled by the structure that gives the cell its shape, the cytoskeleton. Unlike the body’s skeleton of bones, which is hard and static, the cytoskeleton has a dynamic structure that is constantly being built up and broken down. 

Elena Faustini is the first author of the study.
Photo Credit: Emma Busk Winquist

Furthermore, the researchers altered the nuclear membrane using a combination of genetic and chemical methods to make it more flexible. The result: the cell-killing effect of PARP inhibitors increased. The reason for this is that when the nuclear membrane is more flexible, the DNA breaks caused by the PARP inhibitor move around more within the nucleus and therefore the risk that they are not repaired correctly increases, which in turn reduces cancer cell survival. 

The discovery that a more flexible cell nucleus increased the effect of treatment led the researchers to test a combination of PARP inhibitors and a drug that makes the nuclei stiffer. Paclitaxel (marketed under several brand names, including Taxol), prevents the cytoskeleton from being reshaped and has been used for many decades to kill cancer cells. Clinical studies have suggested that when Taxol and PARP inhibitors are combined in cancer treatment, the effect is not improved, but rather worsened. The LiU researchers’ experiments help explain these observations. 

“In one type of cultured cancer cell, the treatment effect of PARP inhibitors was reduced when we simultaneously treated the cells with Taxol. Taxol makes the cell nucleus stiffer, which makes the cells more resistant to treatment with PARP inhibitors. So, combining these drugs with each other is probably not a good idea,” says Francisca Lottersberger. 

Funding: The study was funded by the Swedish Research Council, the Swedish Cancer Society and the Knut and Alice Wallenberg Foundation. 

Published in journal: Nature Communications

Title: Nuclear deformability increases PARPi sensitivity in BRCA1-deficient cells by increasing microtubule-dependent DNA break mobility

Authors: Elena Faustini, Angela dello Stritto, Andrea Panza, Ylli Doksani, and Francisca Lottersberger

Source/Credit: Linköping University | Karin Söderlund Leifler

Reference Number: ongy120125_01

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