Researchers have used custom-made kidney organoids to uncover which cells cause tumors in patients with tuberous sclerosis complex (TSC). They found that kidney tumors in these patients start in Schwann cell precursors. In addition, they determined a single mutation in one of the key genes affected in the disease (TSC1 or TSC2) can affect the development of many different kinds of cells, which explains the variation in kidney tumors even within the same patient.

“The cells at the origin of tuberous sclerosis tumors have been a mystery for decades,” said senior author Bill Sanford, a senior scientist at The Ottawa Hospital and professor at the University of Ottawa. “Our results can help find possible treatment targets for this challenging disease.”

The study findings were published this week in Cell Reports.

Although a relatively new approach, organoids are widely used in cancer research already, including areas such as BRCA-positive ovarian cancer and appendiceal cancer. In this case, it required special steps to create a useful model.

TSC is a rare genetic disease that affects about 40,000 to 60,000 people in the US and 1 in 20,000 people in Europe. It causes benign tumors in the skin, brain, kidneys, heart or lungs. These tumors are very diverse, arising in children or adults with a range of symptoms from mild to life-threatening and often include seizures and kidney problems. There is no cure and treatment options are limited.

“Kidney disease is the leading cause of death in patients with TSC. Around 60 to 80 percent of patients develop tumors in their kidneys, often reducing kidney function and sometimes leading to catastrophic bleeding,” said lead author Adam Pietrobon, an MD-PhD student at The Ottawa Hospital and the University of Ottawa. “There were no adequate lab models to study how TSC affects the kidney, so we made one ourselves.”

Despite a well-described monogenic etiology, the cellular pathogenesis of TSC remains elusive. The disease is caused by mutations in the TSC1 or TSC2 gene. For most patients, these mutations arise spontaneously during development or early life rather than being inherited from their parents. While lab researchers often use animals to study human diseases, there has been no animal model that fully captured TSC’s impact on the kidneys.

TSC tumors in the kidney are puzzling because they are extraordinarily diverse in size, cellular makeup and gene expression, even within the same patient. What causes this diversity was unknown, and it makes treatment challenging. The most common lesions are cysts and angiomyolipomas. One patient may have several such lesions and a small percent of patients will develop cancerous tumors.

To better understand the impact of TSCs on the kidneys, the team grew 3D kidney tissue in the lab from human stem cells that were genetically engineered to have a TSC1 or TSC2 mutation. Known as organoids, these miniature, simplified versions of kidneys had a genetic profile similar to TSC tumors found in patients. The researchers then took single cells from these kidney organoids and injected them into the kidneys of mice, where they grew into human TSC tumors.

“Not only can these ‘mini-kidneys’ help us to better understand this disease, they can also be used to test new therapies,” said Pietrobon.

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