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MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression.

Timothy J Aikin1,2,3, Amy F Peterson1,2,3, Michael J Pokrass1,2,3

  • 1Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, United States.

Elife
|September 17, 2020
PubMed
Summary
This summary is machine-generated.

Cancer mutations alter Mitogen Activated Protein Kinase (MAPK) signaling dynamics, affecting cell behavior. Temporal patterns of ERK activity, either pulsatile or sustained, dictate cell proliferation or arrest and influence neighboring cells.

Keywords:
biosensorscancer biologycell biologyhumanlive-cell imagingsignaling dynamics

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Area of Science:

  • Cell Biology
  • Cancer Research
  • Signal Transduction

Background:

  • Genetic alterations in the Mitogen Activated Protein Kinase (MAPK) pathway are common in human cancers.
  • MAPK signaling dynamics, or temporal patterns of activity, differentially regulate cell behavior.
  • The role of signaling dynamics in mediating cancer-driving mutations remains underexplored.

Purpose of the Study:

  • To investigate how oncogene-induced MAPK signaling dynamics influence cell-autonomous and non-cell-autonomous effects.
  • To determine the specific cellular behaviors associated with pulsatile versus sustained ERK activity.
  • To elucidate the mechanisms by which sustained ERK activity impacts neighboring cells.

Main Methods:

  • Induction of oncogenes to observe resulting ERK activity patterns (pulsatile vs. sustained).
  • Analysis of cellular phenotypes including proliferation and cell cycle arrest.
  • Investigation of intercellular signaling using techniques to study ERK activity waves, ADAM17, and EGFR.
  • Assessment of cell migration and extrusion in response to oncogenic signaling.

Main Results:

  • Oncogene expression results in either pulsatile or sustained ERK activity, correlating with proliferation or cell cycle arrest, respectively.
  • Sustained ERK activity, but not pulsatile, induces ERK activity waves in neighboring cells via ADAM17 and EGFR.
  • The ADAM17-EGFR axis mediates neighboring cell migration towards oncogenic cells and is crucial for oncogenic cell extrusion.
  • Temporal dynamics of MAPK signaling dictate both cell-intrinsic and extrinsic responses to oncogene expression.

Conclusions:

  • The temporal pattern of MAPK activity is a critical determinant of cellular responses to oncogenic mutations.
  • Sustained ERK signaling triggers paracrine signaling cascades that influence the tumor microenvironment.
  • Understanding these dynamics offers new insights into cancer progression and potential therapeutic strategies targeting cell-cell communication.