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Mutations in the epidermal growth factor receptor (EGFR) are common innon-small cell lung cancer (NSCLC), particularly in never-smoker patients.However, these mutations are not always carcinogenic, and have recently beenreported in histologically normal lung tissue from patients with and withoutlung cancer. To investigate the outcome of EGFR mutation in healthy lung stemcells, we grew murine alveolar type-II organoids monoclonally in a 3D Matrigel.Our experiments showed that the \textit{EGFR-L858R} mutation induced a changein organoid structure: mutated organoids displayed more `budding', incomparison to non-mutant controls, which were nearly spherical. We performon-lattice computational simulations, which suggest that this can be explainedby the concentration of division amongst a small number of cells on the surfaceof the organoid, which may arise from several possible biological mechanisms.These results suggest that the L858R mutation produces structures which expandquickly from surface protrusions. We are currently unable to distinguish thecell-based mechanisms that lead to this spatial heterogeneity in growth, butsuggest a number of future experiments which could be used to do so. We suggestthat the likelihood of L858R-fuelled tumorigenesis is affected not just byrandom fluctuations in cell fitness, but by whether the mutation arises in aspatial environment that allows mutant cells to reproduce without being forcedto encounter each other. These data may have implications for cancer preventionstrategies and for understanding NSCLC progression.

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