HMN 2025: What is the potential link between nuclear spot patterns and cancer treatment outcomes

Fighting cancer can feel like a deadly game of chance. Although some patients respond well to certain treatments, others may not be so lucky. Doctors and scientists have long struggled to explain why. Now, Cold Spring Harbor Laboratory (CSHL) assistant professor Katherine Alexander and University of Pennsylvania professor Shelley Berger have discovered a possible source of this variability in clear cell renal cell carcinoma (ccRCC), the cancer of the kidney most commonly diagnosed in adults.

Alexander identified two different patterns of cellular structures called nuclear spots in kidney tumors. More interestingly, Alexander’s research, conducted in Berger’s lab at the University of Pennsylvania, shows a potential correlation between stain patterns and patient outcomes.

“We found that different therapies are more or less effective depending on the appearance of the spots. This means that potentially, if a patient presents with a normal or aberrant spotting condition, they might be more responsive to a medication or to another. Of course, more research needs to be done,” says Alexander.

Discovered over 100 years ago, nuclear spots are tiny cellular structures residing in the nucleus. Here, they are thought to mingle with DNA and help regulate gene activity. Alexander’s research reveals that nuclear spots have two different signatures in ccRCC: normal and aberrant. It’s a question of positioning. Normal spots tend to cluster toward the center of the core. Aberrant spots are more dispersed.

“How these signatures affect patient outcomes remains a mystery for now,” says Berger. “However, the search for answers could lead to more personalized treatments. This discovery offers a new starting point for ccRCC.”

“This is the first suggestion that this would potentially be applicable to giving someone [diagnosed with ccRCC] one medication or another. This is huge because cancer treatment has many horrible side effects. Being able to say to a patient, ‘Your tumor looks like this, so we think this drug will work better than this one,’ is something we really need,” Alexander adds.

The team didn’t just look at kidney cancer. They analyzed the spots in more than 20 different types of cancer, from melanoma to breast cancer. However, only ccRCC showed a correlation between stain patterns and patient outcomes. What makes this cancer special? Alexander’s findings point to HIF-2?, a protein typically overactive in ccRCC. The Alexander laboratory intends to continue on this path alongside other researchers from the CSHL Cancer Center.

For now, Alexander continues to investigate the mystery of the role of nuclear spots in cancer. Although she is in uncharted territory, the object of her research is clear. His work aims to put all the odds in favor of cancer patients.