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arXiv · 2303.11342

An agent-based modelling framework to study growth mechanisms in EGFR-L858R mutant alveolar type II cells

Helena Coggan·Clare E. Weeden·Philip Pearce·Mohit P. Dalwadi·Alastair Magness·Charles Swanton·Karen M. Page
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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 grew murine alveolar type-II organoids monoclonally in a 3D Matrigel. Our experiments showed that the \textit{EGFR-L858R} mutation induced a change in organoid structure: mutated organoids displayed more `budding', in comparison to non-mutant controls, which were nearly spherical. We perform on-lattice computational simulations, which suggest that this can be explained by the concentration of division amongst a small number of cells on the surface of the organoid, which may arise from several possible biological mechanisms. These results suggest that the L858R mutation produces structures which expand quickly from surface protrusions. 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 not just by random fluctuations in cell fitness, but by whether the mutation arises in a spatial environment that allows mutant cells to reproduce without being forced to encounter each other. These data may have implications for cancer prevention strategies and for understanding NSCLC progression.

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Helena Coggan, Clare E. Weeden, Philip Pearce, Mohit P. Dalwadi, Alastair Magness, Charles Swanton, Karen M. Page. 2023-03-20. An agent-based modelling framework to study growth mechanisms in EGFR-L858R mutant alveolar type II cells. https://arxiv.org/abs/2303.11342

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