Defective apical extrusion signaling contributes to aggressive tumor hallmarks

Elife. 2015 Jan 26;4:e04069. doi: 10.7554/eLife.04069.

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.

Keywords: carcinoma; cell biology; epithelial; extrusion; human; human biology; invasion; medicine; mouse; pancreatic; tumor initiation; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Aggregation / drug effects
  • Cell Line, Tumor
  • Cell Polarity* / drug effects
  • Dogs
  • Embryo, Nonmammalian / drug effects
  • Embryo, Nonmammalian / pathology
  • Epidermis / drug effects
  • Epidermis / embryology
  • Epidermis / pathology
  • Epithelial Cells / drug effects
  • Epithelial Cells / pathology
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Humans
  • Madin Darby Canine Kidney Cells
  • Models, Biological
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Lysosphingolipid / metabolism
  • Signal Transduction* / drug effects
  • Zebrafish / embryology

Substances

  • Protein Kinase Inhibitors
  • Receptors, Lysosphingolipid
  • Focal Adhesion Protein-Tyrosine Kinases