title: Defective apical extrusion signaling contributes to aggressive tumor hallmarks.
abstract: 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.
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, United States.
authors.forename: Yapeng
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Surgery, University of Utah, Salt Lake City, United States.
authors.forename: Jill
authors.initials: J
authors.lastname: Shea
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, United States.
authors.forename: Gloria
authors.initials: G
authors.lastname: Slattum
authors.affiliation: Department of Surgery, University of Utah, Salt Lake City, United States.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Firpo
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: Alexander
authors.affiliation: Department of Surgery, University of Utah, Salt Lake City, United States.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Mulvihill
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, United States.
authors.forename: Vita M
authors.initials: VM
authors.lastname: Golubovskaya
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, United States.
authors.forename: Jody
authors.initials: J
authors.lastname: Rosenblatt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology; D002449:Cell Aggregation / Q000187:drug effects; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000187:drug effects; D004285:Dogs; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000473:pathology; D004817:Epidermis / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology
chemical_list: D047428:Protein Kinase Inhibitors; D049349:Receptors, Lysosphingolipid; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: carcinoma; cell biology; epithelial; extrusion; human; human biology; invasion; medicine; mouse; pancreatic; tumor initiation; zebrafish