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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 EGFR-L858R mutation induced a change inorganoid structure: mutated organoids displayed more `budding', in comparisonto non-mutant controls, which were nearly spherical. On-lattice computationalsimulation suggested that this can be explained by an increase in reproductivefitness combined with inhibitory neighbour-neighbour signalling in mutatedorganoids. We predict that these effects prohibit division by cells in theinterior of the organoid and boost the fitness of cells on the surface, sincethis differential growth is sufficient to cause `budding' structures in oursimulations. These results suggest that the L858R mutation produces structureswhich expand quickly from surface protrusions. We suggest that the likelihoodof L858R-fuelled tumorigenesis is affected not just by random fluctuations incell fitness, but by whether the mutation arises in a spatial environment thatallows mutant cells to reproduce without being forced to encounter each other.These data may have implications for cancer prevention strategies and forunderstanding NSCLC progression.

Simulations of 3D organoids suggest inhibitory neighbour-neighbour  signalling as a possible growth mechanism in EGFR-L858R mutant alveolar type  II cells