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Mathematical model of STAT signalling pathways in cancer development and optimal control approaches

Jonggul Lee1, Donggu Lee2, Yangjin Kim2,3,4

  • 1Pierre Louis Institute of Epidemiology and Public Health, Paris 75012, France.

Royal Society Open Science
|October 11, 2021
PubMed

Insights

This study models how the STAT signaling network controls cancer cell death, revealing bi-stability for apoptosis or anti-apoptosis. Mathematical insights inform novel anti-cancer strategies using IFN-β and DDP for improved tumor control.

Area of Science:

  • Molecular Biology and Immunology
  • Mathematical Modeling of Biological Systems
  • Cancer Therapeutics

Background:

  • The Signal Transducer and Activator of Transcription (STAT) family plays crucial roles in immune responses and cell death pathways.
  • The precise mechanisms by which JAK-STAT signaling regulates cancer cell death and tumor growth remain incompletely understood.
  • Understanding intracellular signaling networks is key to developing effective anti-cancer therapies.

Purpose of the Study:

  • To investigate the role of the intracellular signaling network (STAT1, STAT3, Bcl-2, BAX) in regulating cancer cell apoptosis or anti-apoptosis.
  • To develop a mathematical framework to model the bi-stability of this network and its impact on tumor cell fate.
  • To design and optimize anti-tumor strategies, including combination therapies with IFN-β and JAK2 inhibitors (DDP).

Main Methods:

  • Adaptation of a mathematical framework to model the STAT signaling network and its bi-stability.
  • Development of anti-tumor strategies based on the mathematical model, including IFN-β infusion.
  • Application of optimal control theory to maximize anti-tumor efficacy and minimize treatment costs.

Main Results:

  • The mathematical model successfully illustrates how the STAT signaling network can achieve bi-stability, inducing either apoptosis or anti-apoptosis in tumor cells.
  • The study identifies optimal administration sequences for IFN-β and DDP, suggesting improved clinical infusion strategies for combination anti-cancer agents.
  • Optimization strategies were found to minimize tumor volume and maximize apoptotic potential by modulating Bcl-2 and BAX levels while reducing drug dosage.

Conclusions:

  • The JAK-STAT signaling pathway is a critical regulator of cancer cell death programs and tumor growth.
  • Mathematical modeling provides valuable insights into the complex intracellular signaling dynamics and the efficacy of anti-cancer drugs.
  • This research offers a framework for optimizing combination therapy strategies to enhance anti-tumor efficacy and reduce treatment burden.
Keywords:
STAT1apoptosiscancermathematical modeloptimal control

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