Study Reveals Cell Nucleus Shape Influences Cancer Drug Efficacy

Research conducted at Linköping University in Sweden has revealed that the shape of a cell nucleus significantly impacts the effectiveness of cancer therapies. The study indicates that cancer cells with easily deformable nuclei show increased sensitivity to DNA-damage-inducing drugs, particularly PARP1 inhibitors. Published in the journal Nature Communications, the findings also provide insight into why certain drug combinations may yield unexpected results in treatment efficacy.

PARP1 inhibitors have gained prominence in cancer treatment over the past few years. These drugs target cells with mutations in genes responsible for DNA repair, such as the BRCA1 gene. Mutations in BRCA1 substantially elevate the risk of various cancers, prompting some women to opt for preventive surgeries, including mastectomies and oophorectomies. While PARP1 inhibitors are effective for many patients with breast, ovarian, pancreatic, and prostate cancers, resistance to these drugs often develops, particularly in advanced stages where cancer has metastasized.

The researchers aimed to understand the connection between nuclear shape and treatment resistance. Historically, scientists have noted that cancer cells often possess abnormally shaped nuclei, an early indicator of malignancy. This study establishes that the deformation of the nucleus occurs as a response to DNA damage and that cancer cells with more deformed nuclei exhibit greater susceptibility to PARP1 inhibitors.

Francisca Lottersberger, an associate professor at Linköping University, stated, “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 discovery raises the intriguing possibility of using molecules that enhance nuclear deformability to improve therapeutic outcomes.

Impact of Nuclear Flexibility on Treatment

The study highlights the role of the cytoskeleton, the cell’s internal structure that maintains its shape. Unlike the rigid human skeleton, the cytoskeleton is dynamic and constantly changing. The researchers employed genetic and chemical techniques to modify the nuclear membrane, enhancing its flexibility. This modification resulted in increased cancer cell death in response to PARP1 inhibitors. The flexibility allows DNA breaks caused by these drugs to move more freely within the nucleus, increasing the likelihood of improper repair and ultimately reducing cancer cell survival.

Interestingly, the research team also explored the effects of combining PARP inhibitors with Paclitaxel, a well-established chemotherapy drug. Clinical studies have suggested that this combination does not enhance treatment efficacy and may, in fact, worsen outcomes. The findings from this study provide a potential explanation for this phenomenon.

In experiments, the researchers observed that treatment with Taxol, which stiffens the cell nucleus, led to reduced effectiveness of PARP inhibitors in certain cultured cancer cells. Lottersberger concluded, “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.”

The implications of these findings are significant for cancer therapy strategies, as they underscore the importance of understanding the physical properties of cancer cells. Future research may focus on developing treatments that either enhance nuclear deformability or carefully select drug combinations to avoid counterproductive effects.

This study was funded by the Swedish Research Council, the Swedish Cancer Society, and the Knut and Alice Wallenberg Foundation. The research team emphasizes that further investigation is necessary to translate these laboratory findings into clinical applications that could improve patient outcomes in cancer treatment.