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Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction

Jia-Yun Chen1, Clemens Hug2, José Reyes3

  • 1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.

Cell Reports
|March 15, 2023
PubMed

Insights

Aberrant oncogene expression causes cell cycle arrest, but responses vary. This study reveals how BRAF-driven ERK signaling heterogeneity dictates proliferation versus senescence in human epithelial cells, clarifying oncogenic induction outcomes.

Area of Science:

  • Cell Biology
  • Oncology
  • Molecular Biology

Background:

  • Oncogene-induced senescence (OIS) is a tumor-suppressive mechanism where cells cease proliferation due to oncogene activation.
  • Phenotypic heterogeneity is observed in OIS, with some cells senescing while others remain proliferative, but the underlying causes are not fully understood.
  • Understanding OIS heterogeneity is crucial for cancer research and therapeutic development.

Purpose of the Study:

  • To investigate the sources of heterogeneity in human epithelial cell responses to oncogenic BRAFV600E expression.
  • To elucidate the relationship between BRAF-driven ERK signaling activity and cell proliferation/senescence.
  • To characterize distinct cellular response classes to oncogenic signaling.

Main Methods:

  • Induction of oncogenic BRAFV600E in human epithelial cells.
  • Population-level and single-cell assays to measure ERK activity and proliferation.
  • Gene expression profiling across a range of ERK activities over time.

Main Results:

  • A narrow range of BRAFV600E expression resulted in a broad spectrum of downstream ERK activities.
  • ERK activity showed a non-monotonic relationship with proliferation, with intermediate levels promoting maximal proliferation.
  • Four distinct ERK response classes were identified, suggesting a coordinated role in generating heterogeneous proliferation outcomes.

Conclusions:

  • The study maps the input-output relationship between ERK activity and cell proliferation during oncogene induction.
  • Heterogeneity in oncogene-induced senescence arises from variations in downstream signaling dynamics, specifically ERK activity.
  • These findings provide a mechanistic framework for understanding cellular responses to oncogenic stress.
Keywords:
BRAF(V600E)CP: CancerERKcell cycleheterogeneitynon-monotoniconcogene-induced senescenceproliferation

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