PhD candidate develops world’s first mini adrenomedullary tumour

PhD candidate Marit van den Berg is the first in the world to successfully grow a miniature version of a canine adrenomedullary tumour in the laboratory: a so-called pheochromocytoma organoid. This breakthrough marks an important first step toward a model that may be used in the future to test new drugs for both dogs and humans. In her PhD research, Van den Berg studied several aspects of canine pheochromocytomas, leading to improved diagnostics, more accurate prognoses, and new potential drug targets. She will defend her PhD on November 25, under the supervision of promotor prof. dr. Hans Kooistra and co-promotor dr. Sara Galac.

Pheochromocytomas are tumours of the adrenal medulla that produce excess stress hormones such as epinephrine and norepinephrine. This can lead to serious complications such as high blood pressure and cardiac arrhythmias. In humans, pheochromocytomas are rare, but in dogs the condition appears to be considerably more common than long assumed. While pheochromocytomas are well studied in humans, relatively little was known about how they arise and behave in dogs. Aside from surgical removal, which is not always feasible, effective treatments are lacking.

Improved diagnosis

Van den Berg conducted extensive research into pheochromocytomas in dogs, which, in the first place, led to faster and more reliable diagnosis. A key improvement is the ability to interpret a commonly used blood test more accurately. This test measures levels of stress hormone breakdown products, but until now, reference values for healthy dogs were unavailable. Van den Berg has now established these reference ranges, allowing veterinarians to interpret test results with far greater confidence. Thanks to improved diagnostics, it is increasingly clear that pheochromocytomas are far less rare in dogs than previously thought.

Dogs with a high Ki67 score should be monitored more closely so that metastases or tumour recurrence can be detected at an early stage

Better prognosis

Surgical removal is an effective treatment, but in some dogs the tumour can recur or spread. Van den Berg therefore looked for features in tumour tissue that could predict which patients are at higher risk. She found that the Ki67 index, an indicator of cell proliferation, is a reliable predictor of recurrence or metastasis. “There are currently no standardised protocols for post-operative follow-up,” she explains. “Dogs with a high Ki67 score should be monitored more closely so that metastases or tumour recurrence can be detected at an early stage.” Early detection is also essential for future effective treatment, especially as new therapeutic options become available.

New therapeutic targets

Her research also uncovered new leads for future medical treatments. Using genetic and metabolomic analyses, Van den Berg identified two key factors, the RET proto-oncogene and the dopamine D2 receptor, that seem to play a similar role in dogs as in humans with this tumour type. Because medications targeting these pathways already exist for humans, they offer promising starting points for exploring medical treatment options for dogs.

Mini adrenomedullary tumour

Van den Berg’s most groundbreaking achievement is the successful cultivation of canine pheochromocytoma organoids, the first ever grown worldwide. These three-dimensional mini tumours retain important characteristics of the original tumour. “These tumours are exceptionally difficult to maintain in culture; many research groups have tried,” she says. “Our success was likely due to our experience with organoids from other hormone-producing organs and our direct access to fresh tumour tissue in the clinic. It was truly a team effort.”

In the future, these organoids could serve as patient-specific ‘avatars,’ allowing new drugs to be tested before being administered to the animal itself. The model may also benefit human medicine. Current drug testing relies heavily on mouse and rat models, which differ biologically from humans, whereas dogs resemble us more closely. Culturing organoids from human tumours has so far not been successful, and tissue availability is extremely limited because the disease is so rare.
 

Thanks to this research, real hope is emerging for future generations of dogs and humans affected by this disease

Follow-up research

Van den Berg has now begun follow-up work. Over the next eighteen months, she will focus on further optimizing the organoid cultures so they can be used reliably in research and eventually in clinical applications. This includes accelerating cell growth in culture and preserving the tumour’s original characteristics.

Because pheochromocytomas in humans are known to be among the most hereditary cancer types, she is also studying the genetic mutations that increase the risk of these tumours in dogs. Identifying such mutations could facilitate targeted drug therapy and may also provide insight into breed-related risk. In the future, genetic testing could support responsible breeding practices and help reduce the incidence of these tumours.  

“What was once considered a rare tumour in dogs is now known to be far more common”, Van den Berg concludes. “Thanks to this research, real hope is emerging for future generations of dogs and humans affected by this disease.”