What makes pancreatic cancer tumors grow?
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A metabolic cross-talk pathway between cancer and noncancer cells in pancreatic tumors delivers an alternative nutrient to the cancer cells, facilitating tumor growth.
Inside a pancreatic tumor is a hostile environment. Cancer cells are choked off from the blood vessels, blocking access to oxygen and nutrients.
"In principle, you would not expect cells to be able to survive under these circumstances, but in fact they thrive. They are highly adaptable and find ways to cope in this harsh environment," says Costas Lyssiotis, Ph.D., assistant professor of physiology and medicine at the University of Michigan.
His team has discovered one key to how this happens. It’s a metabolic cross talk in which cancer cells call out for nutrients, and nearby normal cells in the pancreas, called pancreatic stellate cells, feed the cancer. The food, in this case, is the amino acid alanine. Their study is published in Nature.
Typically, cells feed on certain types of nutrients. Lipids and carbohydrates like glucose are common examples. But when those aren’t available, researchers showed, cancer finds other options.
"Alanine is an alternative fuel that the cancer co-opts. By expanding the profile of nutrients that cancer cells utilize for growth and survival, they gain a competitive advantage," Lyssiotis says. The process at work
The process at work
In both cell models and mice, the researchers showed that a process called autophagy is required for the metabolic cross talk that turns alanine into a fuel source. Autophagy is a cellular recycling process that degrades old, damaged cargo, like organelles or protein. In this metabolic pathway, the cancer cells release a signal to the pancreatic stellate cells to engage autophagy, which results in protein degradation and alanine release. The cancer cells capture this alanine and use it to grow.
In mouse models, when the researchers blocked autophagy in the stellate cells, it blocked this cross talk and slowed the growth of the tumor.
Pancreatic cancer is one of the most lethal types of cancers. It’s typically aggressive and does not respond well to traditional chemotherapy and radiation treatments. It’s expected to be the second-leading cause of cancer deaths by 2030. New treatments are desperately needed.
The researchers think understanding these metabolic adaptations in pancreatic tumors will lead to new types of therapies that target how cancer cells absorb and use nutrients. Unlike classical treatment strategies that target the cancer cells directly, this process attacks the support cells and opens up new ideas about combination therapies.
"With this new understanding of how and where the cancer cells are obtaining nutrients, our goal now is to design drugs that block this process and hopefully make a difference in this challenging disease," Lyssiotis says.
Additional U-M authors are Christopher J. Halbrook, Li Zhang and Daniel Kremer. Other authors are Cristovao M. Sousa, Douglas E. Biancur, Xiaoxu Wang, Mara H. Sherman, Rosa F. Hwang, Agnes K. Witkiewicz, Haoqiang Ying, John M. Asara, Ronald M. Evans, Lewis C. Cantley and Alec C. Kimmelman.
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