By determining what goes missing in human cells when the gene that is most commonly mutated in pancreatic cancer gets turned on, Johns Hopkins scientists have discovered a potential strategy for therapy.
The production of a particular cluster of genetic snippets known as microRNAs is dramatically reduced in human pancreatic tumor cells compared to healthy tissue, the researchers report in a study published on Dec. 15 in Genes and Development. When the team restored this tiny regulator, called miR-143/145, back to normal levels in human pancreatic cancer cells, those cells lost their ability to form tumors.
"Our finding that these specific microRNAs are downstream of the most important oncogene in pancreatic cancer sets the stage for developing methods to deliver them to tumors," says Josh Mendell, an associate professor in the McKusick-Nath-ans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, and an early career scientist of the Howard Hughes Medical Institute.
"When we restore microRNAs to cancer cells in which their levels are repressed, the cells no longer are tumorigenic. We have every reason to believe that the efficient delivery of miR-143/145, if achievable, would be therapeutically beneficial."
The researchers conducted their studies in a multitude of model systems — human cells growing in culture, as well as those harvested directly from tumors, and also in mice and zebrafish.
"It is likely that some microRNAs will have very broad antitumorigenic effects in many different types of cancers," says Mendell, whose lab is building animal models to investigate how different microRNAs participate in different tumor types. "In fact, there is already evidence that miR-143/145 can suppress other types of tumors, such as colon and prostate cancer. On the other hand, the effects of some microRNAs will likely be very tumor-specific."
Adds Mendell: "We need a better understanding of their basic functions to more fully understand how microRNAs participate in diseases."