PUBLICATION

Defective apical extrusion signaling contributes to aggressive tumor hallmarks

Authors
Gu, Y., Shea, J., Slattum, G., Firpo, M.A., Alexander, M., Mulvihill, S.J., Golubovskaya, V.M., Rosenblatt, J.
ID
ZDB-PUB-150127-2
Date
2015
Source
eLIFE   4: e04069 (Journal)
Registered Authors
Keywords
carcinoma, cell biology, epithelial, extrusion, human, human biology, invasion, medicine, mouse, pancreatic, tumor initiation, zebrafish
MeSH Terms
  • Animals
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Apoptosis/drug effects
  • Protein Kinase Inhibitors/pharmacology
  • Cell Polarity*/drug effects
  • Receptors, Lysosphingolipid/metabolism
  • Focal Adhesion Protein-Tyrosine Kinases/antagonists & inhibitors
  • Focal Adhesion Protein-Tyrosine Kinases/metabolism
  • Cell Aggregation/drug effects
  • Epithelial Cells/drug effects
  • Epithelial Cells/pathology
  • Pancreatic Neoplasms/metabolism*
  • Pancreatic Neoplasms/pathology*
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/pathology
  • Carcinoma, Pancreatic Ductal/metabolism
  • Carcinoma, Pancreatic Ductal/pathology
  • Cell Line, Tumor
  • Dogs
  • Zebrafish/embryology
  • Madin Darby Canine Kidney Cells
  • Signal Transduction*/drug effects
  • Models, Biological
  • Epidermis/drug effects
  • Epidermis/embryology
  • Epidermis/pathology
  • Humans
(all 28)
PubMed
25621765 Full text @ Elife
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.
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
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Citation
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.