Researchers have developed a new fluorescent label that gives a clearer picture of how DNA architecture is disrupted in cancer cells. The findings could improve cancer diagnoses for patients.

Their findings are published in Science Advances in a paper titled, “Ultrastructural visualization of chromatin in cancer pathogenesis using a simple small-molecule fluorescent probe.”

“Imaging chromatin organization at the molecular-scale resolution remains an important endeavor in basic and translational research,” the researchers wrote. “Stochastic optical reconstruction microscopy (STORM) is a powerful superresolution imaging technique to visualize nanoscale molecular organization down to the resolution of ~20 to 30 nm. Despite the substantial progress in imaging chromatin organization in cells and model systems, its routine application on assessing pathological tissue remains limited.”

Yang Liu, PhD, associate professor of medicine and bioengineering at the University of Pittsburgh and member of the UPMC Hillman Cancer Center. [UPMC]

“My lab is focused on developing microscopy techniques to visualize the invisible,” said senior author Yang Liu, PhD, associate professor of medicine and bioengineering at the University of Pittsburgh. “We are one of the first groups to explore the capabilities of superresolution microscopy in the clinical realm. Previously, we improved its throughput and robustness for analysis of clinical cancer samples. Now, we have a DNA dye that is easy to use, which solves another big problem in bringing this technology to patient care.”

Inside the cell’s nucleus, DNA strands are wound around proteins like beads on a string. Pathologists routinely use traditional light microscopes to visualize disruption to this DNA-protein complex, or chromatin, as a marker of cancer or precancerous lesions.

“Although we know that chromatin is changed at the molecular scale during cancer development, we haven’t been able to clearly see what those changes are. This has bothered me for more than 10 years,” said Liu, who is also a member of the UPMC Hillman Cancer Center. “To improve cancer diagnosis, we need tools to visualize nuclear structure at much greater resolution.”

Liu and her team formulated a new label called Hoechst-Cy5 to overcome the hurdle that fluorescent dyes didn’t work well on DNA or in processed clinical cancer samples.

After showing that the new label produced higher resolution images than other dyes, the researchers compared colorectal tissue from normal, precancerous, and cancerous lesions.

The images showed that as cancer progresses, chromatin becomes less densely packed, and the compact structure at the nuclear border is severely disrupted. While these findings indicate that the new label can distinguish normal tissue from precancerous and cancerous lesions, Liu said that superresolution microscopy is unlikely to replace traditional microscopes for such routine clinical diagnoses. Instead, this technology could shine in risk stratification.

To see if chromatin structure could hold clues about future cancer risk, Liu and her team evaluated patients with Lynch syndrome, a heritable condition that increases the risk of several cancer types, including colon cancer. They looked at non-cancerous colorectal tissue from healthy people without Lynch syndrome and Lynch patients with or without a personal history of cancer.

“We see a much larger spread in this group, which is very interesting,” said Liu. “Some patients resemble healthy controls, and some are closer to Lynch patients who previously had cancer. We think that patients with more open chromatin are those who are more likely to develop cancer. We need to follow these patients over time to measure outcomes, but we’re pretty excited that chromatin disruption in normal cells could potentially predict cancer risk.”

In future work, Liu and her team are interested in examining chromatin structure in endometrial tissue from Lynch patients, who also have elevated risk of endometrial cancer. The researchers also received funding recently to look at sputum samples from smokers for early detection of lung cancer.

“We demonstrated the potential of superresolution chromatin imaging in providing new biological insights of nuclear architecture in malignant transformation and the use of nanoscale chromatin structure to risk-stratify patients at a higher risk for developing cancer. This approach opens new opportunities to explore the biological and clinical significance of super-resolved chromatin structure for various diseases,” concluded the researchers.

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