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Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK

Tianchi Xin1, Sara Gallini2, Haoyang Wei2

  • 1Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. tianchi.xin@yale.edu.

Nature Cell Biology
|April 30, 2024
PubMed

Insights

Oncogenic Kras mutations disrupt tissue by altering stem cell signaling. Sustained ERK signaling, not pulsatile, drives abnormal cell behavior and tissue deformation in hair follicles.

Area of Science:

  • Stem cell biology
  • Cancer research
  • Tissue regeneration

Background:

  • Tissue regeneration and maintenance depend on coordinated stem cell behaviors.
  • Oncogenic mutations can impair stem cell orchestration, leading to cancer.
  • Mechanisms by which oncogenes disrupt tissue stem cells remain unclear.

Purpose of the Study:

  • Investigate how oncogenic Kras mutations perturb stem cell orchestration.
  • Elucidate the role of Kras in hair follicle tissue disruption.
  • Understand the signaling dynamics underlying oncogene-induced tissue changes.

Main Methods:

  • Intravital imaging in live mice for longitudinal tracking of hair follicles.
  • Utilized reporter mice to capture real-time ERK signal dynamics at the single-cell level.
  • Investigated the impact of KrasG12D and HrasG12V mutations on tissue and signaling.

Main Results:

  • KrasG12D mutation induces specific spatiotemporal epithelial tissue deformation in hair follicles.
  • This deformation is associated with abnormal cell division and migration.
  • KrasG12D, unlike HrasG12V, converts stem cell ERK signaling from pulsatile to sustained.

Conclusions:

  • Sustained ERK signaling is a key mechanism by which KrasG12D disrupts hair follicle tissue.
  • Interrupting sustained ERK signaling can reverse KrasG12D-induced tissue deformation.
  • Modulating cell migration and division features is crucial for restoring tissue homeostasis.

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