Cancerous perturbations within the ERK, PI3K/Akt, and Wnt/β-catenin signaling network constitutively activate inter-pathway positive feedback loops
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Rahul Rao Padala1, Rishabh Karnawat, Satish Bharathwaj Viswanathan
1Department of Biotechnology, National Institute of Technology Warangal, Warangal, Telangana 506004, India. bikasasim@gmail.com asimbikas@nitw.ac.in.
Abstract:
Perturbations in molecular signaling pathways are a result of genetic or epigenetic alterations, which may lead to malignant transformation of cells. Despite cellular robustness, specific genetic or epigenetic changes of any gene can trigger a cascade of failures, which result in the malfunctioning of cell signaling pathways and lead to cancer phenotypes. The extent of cellular robustness has a link with the architecture of the network such as feedback and feedforward loops. Perturbation in components within feedback loops causes a transition from a regulated to a persistently activated state and results in uncontrolled cell growth. This work represents the mathematical and quantitative modeling of ERK, PI3K/Akt, and Wnt/β-catenin signaling crosstalk to show the dynamics of signaling responses during genetic and epigenetic changes in cancer. ERK, PI3K/Akt, and Wnt/β-catenin signaling crosstalk networks include both intra and inter-pathway feedback loops which function in a controlled fashion in a healthy cell. Our results show that cancerous perturbations of components such as EGFR, Ras, B-Raf, PTEN, and components of the destruction complex cause extreme fragility in the network and constitutively activate inter-pathway positive feedback loops. We observed that the aberrant signaling response due to the failure of specific network components is transmitted throughout the network via crosstalk, generating an additive effect on cancer growth and proliferation.
Insights
Cancer arises from genetic changes disrupting cell signaling pathways. This study models key pathways, revealing how network fragility drives uncontrolled cell growth and proliferation.
Area of Science:
- Molecular biology
- Systems biology
- Cancer research
Background:
- Cellular signaling pathways, including ERK, PI3K/Akt, and Wnt/β-catenin, are crucial for normal cell function.
- Genetic or epigenetic alterations can perturb these pathways, leading to malignant transformation and cancer.
- Network architecture, particularly feedback loops, influences cellular robustness against perturbations.
Purpose of the Study:
- To develop a mathematical and quantitative model of the crosstalk between ERK, PI3K/Akt, and Wnt/β-catenin signaling pathways.
- To analyze the dynamics of signaling responses under genetic and epigenetic changes associated with cancer.
- To elucidate how network perturbations contribute to uncontrolled cell growth and cancer phenotypes.
Main Methods:
- Mathematical and quantitative modeling of signaling pathway crosstalk.
- Analysis of intra- and inter-pathway feedback loops within the ERK, PI3K/Akt, and Wnt/β-catenin networks.
- Simulation of genetic and epigenetic alterations affecting key pathway components (e.g., EGFR, Ras, PTEN).
Main Results:
- Cancer-associated perturbations in key components like EGFR, Ras, B-Raf, PTEN, and the destruction complex lead to significant network fragility.
- Constitutive activation of inter-pathway positive feedback loops was observed due to these perturbations.
- Aberrant signaling responses are transmitted through network crosstalk, amplifying effects on cancer cell growth and proliferation.
Conclusions:
- Network fragility and the activation of feedback loops in signaling pathways are critical mechanisms driving cancer.
- Crosstalk between signaling pathways plays a significant role in the additive effects on cancer progression.
- Mathematical modeling provides insights into the complex dynamics of signaling networks in cancer development.