University of Arizona Comprehensive Cancer Center scientists are building a new origin story for a set of rare gastrointestinal, or GI, tumors, opening new possibilities for identifying drug targets and potential treatments. 

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The research team found evidence suggesting that some gastroenteropancreatic neuroendocrine tumors, or GEP-NETs, may not originate from hormone-secreting endocrine cells. Instead, they could come from neural crest cells, which also give rise to brain cells. The findings, published in Molecular Cancer, may shift the thinking on how the cancers develop.

GEP-NETs are rare, slow-growing cancers. GEP-NETs occur mostly in the small intestine, pancreas and stomach. They are difficult to detect, study and effectively treat, and the number of cases is increasing. Neuroendocrine cancers in the GI tract are the second-most common GI tumor. 

The researchers, led by Dr. Juanita Merchant, chief of the Division of Gastroenterology and Hepatology and Regents Professor of Medicine and Physiology in the U of A College of Medicine – Tucson, used a combination of organoids, cell culture and mouse models to show that pancreatic and small intestine, or duodenal, neuroendocrine tumors may develop from neuron-supporting glial cells in the brain. Organoids are tiny, 3D models of organs and tissues grown from stem cells. 

Merchant said that a tumor’s origin matters for both understanding how a cancer develops and finding ways to treat it. 

“If we can understand where the tumors come from, then maybe we can understand the different signaling pathways it takes to become a cancer,” she said. “Then we can think about identifying a part of that pathway to target and disrupt.”

Merchant noted that it’s generally assumed that most endocrine tumors come from endocrine cells. 

“If some of these neuroendocrine tumors are arising from cells of neural origin as opposed to endocrine origin, then maybe we can think of them as brain cancers, which changes the repertoire of tools to use against them,” she said.

For years, Merchant and her co-workers have studied GI neuroendocrine tumors that carry a mutation in the Men1 gene. Men1, or multiple endocrine neoplasia type one, makes the menin protein. Such tumors are typically made up of diverse cell types. Merchant and her team wanted to better understand the origin of the tumors. 

“The assumption is if they are making hormones and look like endocrine tissues, then the tumors must arise from endocrine tissues. But that’s nearly impossible to prove in people,” she said. 

Several years ago, Merchant’s group found that turning off Men1 activity in a mouse model of a neuroendocrine tumor did not lead to cancer, but rather a condition called hypergastrinemia. Studies showed cells were making gastrin, a hormone. A process called immunohistochemical staining on tumor cells indicated glial cells were responsible. 

According to Merchant, stem cells developing from the nervous system – specifically the spinal cord and an embryologic structure called the neural crest – ultimately must decide whether to become neurons or glial cells. A cell signaling pathway called hedgehog controls the decision. Hedgehog, one of several signaling pathways that play crucial roles in embryonic development, is frequently hijacked by cancer cells. 

“We asked, is hedgehog involved in the decision point for these glial cells to take on a more neuronal phenotype?” Merchant said. “We knew there’s something else also happening because often the cells didn’t become neurons but instead become neuroendocrine cells.” 

Her team studied human duodenal neuroendocrine and pancreatic neuroendocrine tumors and tried to find remnants of hedgehog markers for clues. 

“In the paper, we show that the tumors that were expressing hedgehog markers tended to have a higher mortality,” Merchant said. “Duodenal tumors tend to be more susceptible to the hedgehog signaling pathway. They're more likely to overexpress the hedgehog signaling pathway compared to the pancreatic tumors.” 


The researchers needed to disrupt menin in some way to simulate what was happening in Men1 mutation-driven tumors in the pituitary and pancreas. They studied the effects of turning off menin activity by deleting a gene coding for a protein that’s necessary for hedgehog signaling. 

“This resulted in fewer tumors, which reinforced the idea that hedgehog signaling is necessary to cause the cancers,” Merchant said. 

“Most of the GI neuroendocrine tumors tied to disruption of menin tend to be in the proximal duodenum and are more likely to be malignant and metastasize,” she added. “That might help us understand how to screen patients and possibly help us identify which patients are more likely to develop more dangerous tumors.”

Merchant said that clinicians could consider repurposing U.S. Food and Drug Administration-approved drugs, including some that inhibit hedgehog activity, as potential treatments for these cancers. 

“There are so many new possibilities from our evolving understanding of these cancers.”

Co-authors included Travis Sawyer, assistant professor at the James C. Wyant College of Optical Sciences, and from the College of Medicine – Tucson, undergraduate student AnneLeigh B. Twer, MD/PhD student Ateh Zinkeng, research specialist Ricky A. Sontz, and former postdoctoral fellow Suzann Duan, who is now at the University of California, Irvine.

This study was funded in part by the National Institute of Diabetes and Digestive and Kidney Diseases, a division of the National Institutes of Health, under award no. 5K01DK136969 and the University of Arizona Cancer Center Support Grant P30CA023074.