A Potential Way to Reverse Effects of Some of the Most Deadly Cancers

Huntsman Cancer Institute’s Rosenblatt Lab discovered that disrupting extrusion, a normal process which squeezes cells out of overcrowded epithelial tissues to die, may be a mechanism by which pancreas cancer begins. They may have also identified a way to reverse invasive effects of pancreas cancer that result from defective extrusion without destroying normal tissues nearby.

Epithelial cells line and protect the cavities and surfaces of structures throughout the body, including organs such as the pancreas. Top Science 2012 reported on the lab's discovery of extrusion, which maintains constant, healthy cell numbers. Normally, signaling through the factor sphingosine 1-phosphate receptor 2 (S1P2) triggers the extrusion process.

“Usually cells pop out, away from underlying tissue, to die,” says Rosenblatt. “Looking at zebrafish, we found that when the S1P2 signal is disrupted, cells instead build up and form masses that resist cell death—even when treated by chemotherapy—or they pop into underlying tissue where they can potentially invade. Also, some cells die without being extruded, creating holes in the epithelial barrier, which could cause chronic inflammation that can also promote cancer.”

zebrafish under a microscope

This microscope image shows zebrafish cells lacking the S1P2 receptor that is also missing in pancreatic cancer. The masses develop as a result of cells not extruding to die.

The team found several types of aggressive cancers that resist chemotherapy—pancreatic ductal adenocarcinoma (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 cell death. About 50% of such cells did not extrude, instead forming masses, while most of the remaining cells extruded inward rather than outward.

“This kind of extrusion may be a common hallmark of invasive tumor types,” says Rosenblatt. “While the mechanisms that drive tumor cell invasion are not yet clear, our results suggest that altering the direction cells extrude could allow cells to invade instead of getting expelled out to waste.”

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 the defective extrusion observed in experimental models by using FAK inhibitors. Rosenblatt’s group found simply adding FAK inhibitors returned cell death rates to normal, and surprisingly, also eliminated the large cell masses and improved the barrier function.

“Some FAK inhibitors are already being tested in clinical trials for other types of cancers,” says Rosenblatt. “Hopefully, they may also be a better therapy for recalcitrant tumors such as pancreas cancers and some lung cancers.

“So far, we have focused on tumors that have not spread and on invasive cells in culture. Now we need to see if we can use FAK inhibitors to target cells that have moved to other sites, or metastasized, since metastasis is an important feature of pancreatic cancer. That’s the next phase of our study,” says Rosenblatt.

Yapeng Gu, PhD, and Gloria Slattum, PhD, members of HCI’s Rosenblatt Lab, are co-authors of this article. Other co-authors include Jill Shea, PhD; Matthew Firpo, PhD; Sean Mulvihill, MD; and Margaret Alexander from the University of Utah; and Vita Golubovskaya, PhD, of Roswell Park Cancer Institute in Buffalo, New York. This study was supported by a National Institute of Health Director’s New Innovator Award 1DP2OD002056-01, as well as R01GM102169 and P30CA042014. The University of Utah provided a Funding Incentive Seed Grant and Huntsman Cancer Foundation also provided research support funding.