|ZFIN ID: ZDB-PUB-150127-2|
Defective apical extrusion signaling contributes to aggressive tumor hallmarks
Gu, Y., Shea, J., Slattum, G., Firpo, M.A., Alexander, M., Mulvihill, S.J., Golubovskaya, V.M., Rosenblatt, J.
|Source:||eLIFE 4: e04069 (Journal)|
|Keywords:||carcinoma, cell biology, epithelial, extrusion, human, human biology, invasion, medicine, mouse, pancreatic, tumor initiation, zebrafish|
|PubMed:||25621765 Full text @ Elife|
Gu, Y., Shea, J., Slattum, G., Firpo, M.A., Alexander, M., Mulvihill, S.J., Golubovskaya, V.M., Rosenblatt, J. (2015) Defective apical extrusion signaling contributes to aggressive tumor hallmarks. eLIFE. 4:e04069.
ABSTRACTWhen 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.