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Induction and Analysis of Epithelial to Mesenchymal Transition
10:37

Induction and Analysis of Epithelial to Mesenchymal Transition

Published on: August 27, 2013

38.0K

Epithelial-to-mesenchymal transition rewires the molecular path to PI3K-dependent proliferation

Megan B Salt1, Sourav Bandyopadhyay, Frank McCormick

  • 11Helen Diller Family Comprehensive Cancer Center; 2Biomedical Sciences Graduate Program, University of California San Francisco; and 3California Institute for Quantitative Biosciences, San Francisco, California.

Cancer Discovery
|December 5, 2013
PubMed
Abstract

Insights

Epithelial-to-mesenchymal transition (EMT) alters cell proliferation by changing how phosphoinositide 3-kinase (PI3K) is activated. EMT reduces ERBB3, impacting PI3K signaling and cell growth, which can be overcome by reactivating PI3K.

Area of Science:

  • Cell biology
  • Cancer research
  • Molecular signaling

Background:

  • Epithelial-to-mesenchymal transition (EMT) is linked to cancer metastasis, drug resistance, and poor prognosis.
  • Understanding how EMT impacts cellular proliferation is crucial for developing effective cancer therapeutics.
  • Tumor heterogeneity in EMT status necessitates a detailed examination of molecular requirements for proliferation.

Purpose of the Study:

  • To elucidate the mechanistic changes in phosphoinositide 3-kinase (PI3K) pathway activation during EMT.
  • To investigate how EMT affects the molecular dependencies for cell proliferation.
  • To define the role of ERBB3 in regulating PI3K-dependent proliferation following EMT.

Main Methods:

  • Comparative analysis of PI3K pathway activation in epithelial and mesenchymal cells.
  • Assessment of ERBB3 expression and its impact on autocrine signaling.
  • In vivo studies using mesenchymal tumors to correlate PIK3CA expression with ERBB3 levels.

Main Results:

  • EMT rewires PI3K pathway activation, shifting from ERBB3-dependent signaling in epithelial cells to a state where ERBB3 is downregulated.
  • Loss of ERBB3 after EMT reduces serum-independent proliferation.
  • Reactivation of PI3K signaling through p110α, ERBB3 reexpression, or growth factor stimulation can rescue proliferation.
  • PIK3CA is upregulated in mesenchymal tumors with low ERBB3 expression.

Conclusions:

  • EMT alters cellular proliferative potential by modulating ERBB3 expression.
  • Signaling pathways upstream of proliferation can be rewired by changes in EMT status.
  • Multiple molecular routes can drive proliferation depending on the cell's state, highlighting therapeutic vulnerabilities.

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