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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
An agent-based modelling framework to study growth mechanisms in EGFR-L858R mutant cell alveolar type II cells
Helena Coggan1, Clare E Weeden2, Philip Pearce1,3
1Department of Mathematics, University College London, London, UK.
Abstract:
Mutations in the epidermal growth factor receptor (EGFR) are common in non-small cell lung cancer (NSCLC), particularly in never-smoker patients. However, these mutations are not always carcinogenic, and have recently been reported in histologically normal lung tissue from patients with and without lung cancer. To investigate the outcome of EGFR mutation in healthy lung stem cells, we grow murine alveolar type II organoids monoclonally in a three-dimensional Matrigel. Our experiments show that the EGFR-L858R mutation induces a change in organoid structure: mutated organoids display more 'budding', in comparison with non-mutant controls, which are nearly spherical. We perform on-lattice computational simulations, which suggest that this can be explained by the concentration of division among a small number of cells on the surface of the mutated organoids. We are currently unable to distinguish the cell-based mechanisms that lead to this spatial heterogeneity in growth, but suggest a number of future experiments which could be used to do so. We suggest that the likelihood of L858R-fuelled tumorigenesis is affected by whether the mutation arises in a spatial environment that allows the development of these surface protrusions. These data may have implications for cancer prevention strategies and for understanding NSCLC progression.
Insights
Epidermal growth factor receptor (EGFR) mutations in lung stem cells can alter organoid structure, leading to increased budding. This spatial change may influence the development of non-small cell lung cancer (NSCLC).
Area of Science:
- Oncology
- Molecular Biology
- Biophysics
Background:
- Epidermal growth factor receptor (EGFR) mutations are prevalent in non-small cell lung cancer (NSCLC), especially in never-smokers.
- These mutations have been found in histologically normal lung tissue, suggesting they may not always be immediately carcinogenic.
- The role of EGFR mutations in healthy lung stem cells and their potential to initiate cancer remains unclear.
Purpose of the Study:
- To investigate the functional consequences of EGFR mutations in healthy lung stem cells.
- To understand how specific EGFR mutations, like L858R, affect cell behavior and tissue organization.
- To explore the potential link between EGFR mutation-induced structural changes and non-small cell lung cancer (NSCLC) development.
Main Methods:
- Culturing murine alveolar type II organoids monoclonally in a three-dimensional Matrigel.
- Introducing the EGFR-L858R mutation into organoids.
- Observing and comparing the structural morphology of mutated versus non-mutant organoids.
- Utilizing on-lattice computational simulations to model cell division patterns.
Main Results:
- The EGFR-L858R mutation induced significant structural changes in organoids, characterized by increased 'budding' compared to the spherical shape of non-mutant controls.
- Computational simulations suggested that this budding phenotype arises from concentrated cell division on the organoid surface.
- Spatial heterogeneity in growth was observed, though the precise cell-based mechanisms require further investigation.
Conclusions:
- The spatial environment where an EGFR mutation occurs may influence tumorigenesis.
- EGFR-L858R mutations can alter lung stem cell organoid structure, potentially impacting non-small cell lung cancer (NSCLC) progression.
- These findings may inform future cancer prevention strategies and enhance our understanding of NSCLC development.
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