COLD SPRING HARBOR, N.Y., Jan. 2, 2025 - Fighting cancer can seem like a deadly game of chance. While some patients may respond well to certain treatments, others might not be as fortunate. 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 found a possible source of this variability in clear cell renal cell carcinoma (ccRCC)—the most common kidney cancer diagnosed in adults.

Alexander has identified two different patterns of cellular structures known as nuclear speckles in kidney tumors. Even more exciting, Alexander's research, conducted in Berger's lab at the University of Pennsylvania, shows a potential correlation between speckle patterns and patient outcomes. Alexander explains:

"We found that different therapies are more or less effective depending on how the speckles look. This means potentially if a patient comes in with a normal or aberrant speckle state, they might be more responsive to one drug or another. Of course, more research needs to be done."

Discovered over 100 years ago, nuclear speckles are tiny cellular structures that reside in the nucleus. Here, they're thought to intermingle with DNA and help regulate gene activity. Alexander's research reveals that nuclear speckles have two different signatures in ccRCC: normal-like and aberrant. It's a matter of positioning. Normal-like speckles tend to congregate toward the center of the nucleus. Aberrant speckles are more dispersed.

"How these signatures affect patient outcomes remains a mystery for now," Berger says. "However, the search for answers may lead to more personalized treatments. This discovery offers a new starting point in ccRCC." Alexander adds:

"It's the first suggestion that this would be potentially applicable to giving someone [diagnosed with ccRCC] one drug or another. That's huge because cancer therapy has a lot of horrible side effects. To be able to tell a patient, 'Your tumor looks like this, so we think this drug will work better than this drug,' is something we really need."

The team didn't just look at kidney cancer. They analyzed speckles in over 20 different types of cancers, from melanomas to breast cancer. However, only ccRCC showed a correlation between speckle patterns and patient outcomes. What makes this cancer special? Alexander's findings point to HIF-2