Several types of aggressive cancers, including pancreatic ductal adenocarcinoma (PDAC), may become invasive when a recently discovered cell process called extrusion is defective. Researchers at Huntsman Cancer Institute discovered cell extrusion and now have found an existing drug that may interfere with defective extrusion in PDAC, thus potentially reversing the invasive effects of this deadly cancer type.
Extrusion occurs in epithelial cells, which line and protect the cavities and surfaces of structures throughout the body, including organs such as the pancreas. Jody Rosenblatt and her lab previously showed that in normal epithelial tissues when there are too many cells and it gets overcrowded, a signal through the protein S1P2 (sphingosine 1-phosphate receptor 2) tells some of the cells it is time to be extruded, or be squeezed, out of the tissue. The extruded cells die. When the S1P2 signal is disrupted, cells instead build up and form masses that resist cell deatheven when treated by chemotherapyor they pop into underlying tissue where they can potentially invade.
Rosenblatt and her colleagues recently found that PDAC, lung cancer, and some types of colon cancer have significantly reduced amounts of S1P2. Focusing on PDAC tumor cells, they showed that reduced S1P2 levels led to reduced rates of extrusion and reduced cell death.
By connecting these deadly cancer types to a failure of extrusion, the group was able to look in more detail at the process and to try to find ways to reverse the effects.
Normally, extruded cells die when they separate from the epithelium because they lose access to a signal conveyed by focal adhesion kinase (FAK). The team tested whether they could interfere with defective extrusion observed in experimental models by using FAK inhibitors. What they found is that simply adding FAK inhibitors returned cell death rates to normal, and surprisingly, also eliminated the large cell masses.
Researchers are already testing some FAK inhibitors in clinical trials for other types of cancers and this new work by the Rosenblatt lab suggests some invasive cancers, including PDAC, may also benefit from future testing.
Huntsman Cancer Institute is an NCI-designated cancer research facility and hospital located on the campus of the University of Utah in Salt Lake City, Utah, and meets the highest standards for cancer care and research. HCI serves cancer patients throughout the Intermountain West and provides academic and clinical training for future physicians and researchers. For more information about the Huntsman Cancer Institute, please visit www.huntsmancancer.org.