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.Comment: 18 pages, 10 figure