Pancreatic cancer is expected to become the second-deadliest cancer in the United States by 2030. Many researchers believe that the rise in obesity is a key factor in this increase. A new study led by Yale Cancer Center (YCC) researchers has demonstrated in mice that hormones released from the pancreas itself can advance the cancer—and that weight loss can stop this process in its early stages. The research was published today in the journal Cell.
“These discoveries raise the hope of finding new ways to prevent both the growth and the spread of pancreatic cancer,” said Mandar Muzumdar, M.D., assistant professor of genetics at Yale School of Medicine, a member of the Yale Cancer Biology Institute, and senior author of a paper.
Muzumdar and his collaborators, including a team from the Massachusetts Institute of Technology (MIT), began the project with a mouse model that was genetically modified to develop pre-cancerous pancreatic lesions with a mutation in the KRAS gene, which is mutated in most human pancreatic cancers. The mice also were genetically engineered both to become obese and to rapidly lose weight when scientists administered an additional form of genetic manipulation or limited their food intake.
Unlike mice of normal weight engineered with the KRAS mutation, obese mice with this mutation rapidly developed advanced pancreatic cancer. And unlike most humans diagnosed with the disease, tumors in the model mice did not present additional genetic mutations that would further enable tumor progression. “Just by making them obese, we could essentially simulate the effect of an additional mutation,” Muzumdar said. “That suggested that there is a huge effect of obesity on cancer development in mice.”
Next, he and his colleagues studied whether weight loss could slow the development of cancer in the mice who had developed pre-cancerous lesions. The results were dramatic. “We found that if we made the mice lose weight prior to advanced cancer development, we could essentially block the progression to advanced cancer almost as if they were never obese,” Muzumdar said. “If we made the mice lose weight after advanced cancers had developed, the mice still succumbed to the disease within the same timeframe.”
The finding suggested the possibility of intercepting tumor formation or progression by weight loss, or eventually using novel drugs that target the underlying biological pathways. Muzumdar noted that the result matches up well with clinical studies of people who are given weight-reducing bariatric surgery, which appears to lower the risk of developing pancreatic cancer.
To determine the cause of the tumors in these mice, the team looked at the genes being expressed in clusters of hormone-producing cells called “islets” in their pancreases. One type of pancreatic islet cell known as a “beta cell” normally produces insulin. In these mice, however, some beta cells were churning out a hormone called cholecystokinin (Cck), normally generated in the intestine to aid digestion. These beta cells also seemed to secrete less insulin. This finding interested Muzumdar and his team because they knew that the Cck hormone acts on the digestive enzyme-secreting cells where the predominant type of pancreatic cancer emerges.
They also discovered that Cck expression in the islets dropped when the obese mice lost weight. Additionally, other mouse models that were engineered with the KRAS mutation and forced to express Cck in beta cells, but were not obese, were more likely to form pancreatic tumors than mice engineered with the KRAS mutation alone.
Muzumdar’s lab is now studying why beta cells switch from making insulin to Cck. Another key puzzle is how Cck can boost tumor formation and progression. “Our hope is that the underlying pathways and mechanisms we’re identifying in obesity also may apply to those who develop pancreatic cancer in the absence of obesity,” he added.
Lead authors on the paper include Jaffarguriqbal Singh and Lauren Lawres from Yale and Katherine Minjee Chung and Kimberly Judith Dorans from MIT’s Koch Institute of Integrative Cancer Research. Yale’s Cathy Garcia, Daniel Burkhardt, Rebecca Cardone, Xiaojian Zhao, Richard Kibbey, Smita Krishnaswamy and Charles Fuchs contributed to the study, as did Rebecca Robbins, Arjun Bhutkar and Tyler Jacks from MIT. Other contributors included Ana Babic, Sara Vayrynen, Andressa Dias Costa and Brian Wolpin from Dana-Farber Cancer Institute; Jonathan Nowak from Brigham and Women’s Hospital; Daniel Chang of Stanford Cancer Institute; Richard Dunne and Aram Hezel of the University of Rochester Medical Center; Albert Koong of the University of Texas MD Anderson Cancer Center; Joshua Wilhelm and Melena Bellin of the University of Minnesota Medical Center; and Vibe Nylander, Anna Gloyn and Mark McCarthy of the University of Oxford.
Funding for the study was provided by the Lustgarten Foundation, the National Institutes of Health, and YCC.
Yale School of Medicine