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Oncogenic PIK3CA corrupts growth factor signaling specificity

Ralitsa R Madsen1,2, Alix Le Marois3, Oliwia N Mruk4

  • 1Cell Signaling Laboratory, Department of Oncology, University College London Cancer Institute Paul O'Gorman Building, University College London, London, WC1E 6BT, UK. rmadsen001@dundee.ac.uk.

Molecular Systems Biology
|December 20, 2024
PubMed

Insights

The PIK3CA^H1047R^ oncogene corrupts growth factor signaling, altering phosphoinositide 3-kinase (PI3K)/AKT pathway information transfer and amplifying specific receptor signals. This finding offers new therapeutic strategies for cancer.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Cancer research

Background:

  • Understanding growth factor signal encoding in the phosphoinositide 3-kinase (PI3K)/AKT pathway is limited by technical challenges.
  • The impact of oncogenic mutations on PI3K/AKT pathway signaling fidelity remains unclear.

Purpose of the Study:

  • To develop a kinetic, single-cell framework for quantifying PI3K-specific information transfer.
  • To investigate how the PIK3CA^H1047R^ oncogene alters growth factor signaling and pathway fidelity.

Main Methods:

  • Live-cell imaging of PI3K/AKT activity reporters.
  • Multiplexed CyTOF measurements of PI3K/AKT and RAS/ERK signaling markers.
  • Single-cell kinetic framework for information transfer calculations.

Main Results:

  • The PIK3CA^H1047R^ oncogene does not act as a simple constitutive activator.
  • Dose-dependent PIK3CA^H1047R^ expression corrupted growth factor-induced information transfer fidelity.
  • Preferential amplification of epidermal growth factor receptor (EGFR) signaling over IGF1 and insulin receptor signaling was observed.
  • PIK3CA^H1047R^ increased both the mean and heterogeneity of signaling responses.

Conclusions:

  • Oncogenic PIK3CA^H1047R^ corrupts information transfer in a growth factor-dependent manner.
  • This provides new opportunities for therapeutic intervention by tuning receptor-specific PI3K pathway outputs.
Keywords:
Growth Factor SpecificityInformation TransferPI3K Signaling DynamicsSingle-cell Biology

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