When epithelia become too crowded, some cells are extruded that later die. To extrude, a cell produces the lipid, Sphingosine 1-Phosphate (S1P), which activates S1P2 receptors in neighboring cells that seamlessly squeeze the cell out of the epithelium. Here, we find that extrusion defects can contribute to carcinogenesis and tumor progression. Tumors or epithelia lacking S1P2 cannot extrude cells apically and instead form apoptotic-resistant masses, possess poor barrier function, and shift extrusion basally beneath the epithelium, providing a potential mechanism for cell invasion. Exogenous S1P2 expression is sufficient to rescue apical extrusion, cell death, and reduce orthotopic pancreatic tumors and their metastases. Focal Adhesion Kinase (FAK) inhibitor can bypass extrusion defects and could, therefore, target pancreatic, lung, and colon tumors that lack S1P2 without affecting wild-type tissue.
Epithelial cells cover the surface of our bodies, line our lungs, stomach and intestines and serve as a protective layer around other organs. If too many epithelial cells die and are not replaced, this protective layer may erode and lead to organ damage. However, if too many new cells grow, tumors can form.
One process that helps to maintain the right number of epithelial cells is called extrusion. When too many epithelial cells are present, the resulting overcrowding triggers this process to squeeze excess cells out of the layer and away from the organ. Usually, these cells quickly die. However, if the pathway that regulates this process—which involves a receptor protein called S1P2—is disturbed, the cells may instead be pushed into the space between the epithelial layer and the organ. When this happens, the cells are more likely to survive and may then form a tumor that invades the organ.
Gu et al. interfered with extrusion by reducing the levels of the S1P2 receptor in layers of human epithelial cells grown in the laboratory. Fewer epithelial cells were squeezed out of these cell layers, making the layers up to three times as thick in places. Moreover, mutant zebrafish lacking the S1P2 receptor also accumulated epithelial masses throughout their bodies.
Gu et al. found that disrupting the extrusion process made the cells resistant to chemotherapy, and that certain hard-to-treat human pancreatic, lung, and colon cancers had lower levels of the S1P2 receptors. Boosting the activity of S1P2 receptors helped to restore normal extrusion and reduced the size of pancreatic tumors in mice.
Gu et al. then focused on an enzyme called Focal Adhesion Kinase that helps cells to survive. Treating zebrafish with a drug to block the activity of this enzyme left normal fish unharmed. However, in mutant fish with malfunctioning extrusion pathways, the drug rescued the number of cells that died, reduced the size and number of masses, and cured their leaky skin barrier. If further studies confirm the results, the drug may offer a new, less toxic, treatment for certain cancers that do not respond to currently available treatments.