Lustgarten Foundation-Funded Researchers Discover New Mutations in Pancreatic Cancer

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By closely studying a part of the human genome that has not yet been carefully looked at before in pancreatic cancer cells, researchers supported by the Lustgarten Foundation have found important new clues to the development of pancreatic cancer.

The more that is known about defects in specific pathways in pancreatic cancer, the more options researchers will have for developing new treatment options.

“The new data adds depth to our understanding of things that go awry in critical cellular pathways as a result of mutations, sometimes promoting cancer formation, other times providing cancer cells with advantages that enable them to crowd out healthy cells,” said David Tuveson, M.D., Ph.D., Director of Research for the Lustgarten Foundation and Director of Cold Spring Harbor Laboratory Cancer Center.

The researchers looked for mutations only in small segments of DNA called promoters, in samples of tumors taken from 308 pancreatic cancer patients. Promoters usually lie adjacent to genes whose activity they help regulate.  An activated promoter can switch “on” the gene it sits next to.  One of many causes of cancer are genes that stay “on” for too long, bypassing natural signals to shut down.  This is one way cancers grow out of control.

Using a newly developed algorithm, the team discovered that while the promoter mutations they discovered were not near known pancreatic cancer genes, they affected some of the same biological pathways inside cancer cells.  Prominent among these were promoters affecting pathways that control cell adhesion and axon guidance.

Cell adhesion pathways help determine whether cells stick together or can fly free of the tissue in which they live.  Cancerous cells that do not adhere to moorings in tissue can become the seeds of metastasis—the often deadly situation in which loose cancer cells colonize other parts of the body.

The axon guidance pathway associated with promoter mutations has a less obvious but no less important role in pancreatic cancer.  “In pancreas cancer, nerves are often attracted to or get attracted to the tumor,” explains Michael Feigin, Ph.D., a postdoctoral researcher who led the experiments in the Tuveson lab, “and sometimes they grow right through the tumor.  This is one of the reasons pancreas cancer is so painful.” Tumors, he also notes, can actually spread via nerves; this is called perineural invasion.

It’s possible, Feigin says, that axon guidance signals—and indeed cell adhesion signals— “are actually being used by tumor cells” to gain advantages over healthy cells.

While further exploration is required, the importance of this new knowledge about promoter mutations is that it can help researchers find new ways to fight pancreatic cancer, one of the major cancer types that remains profoundly resistant to all existing treatments.

“Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma” appears May 8th in Nature Genetics. The authors are: Michael E. Feigin, Tyler Garvin, Peter Bailey, Nicola Waddell, David K. Chang, David R. Kelley, Shimin Shuai, Steven Gallinger, John D. McPherson, Sean M. Grimmond, Ekta Khurana, Lincoln D. Stein, Andrew V. Biankin, Michael C. Schatz, and David A. Tuveson. The paper can be accessed at: https://www.ncbi.nlm.nih.gov/pubmed/28481342


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