Tumour Cell Heterogeneity Instructs Fibroblast Diversity and Reciprocal Signalling

Tumours are complex ecosystems where phenotypically diverse tumour cells are embedded in a heterocellular environment. Using an in vitro model of intra-tumoural heterogeneity, we find that clonal tumour cell populations establish disparate interactions with stromal fibroblasts to regulate phenotypic diversity across tumour and stromal cell populations. Unexpectedly, tumour sub-clones instruct stromal fibroblasts to acquire distinct phenotypes, thereby increasing fibroblast diversity, whereas tumour cell diversity is reduced by fibroblast interactions. Heterocellular interactions differentially engage tumour cell reciprocal signalling pathways, resulting in normalisation of cell-autonomous differences in MAPK signalling but diversification of AKT signalling. These results demonstrate that tumour-stroma interactions differentially alter tumour and stromal cell diversity and that our existing cell-autonomous perspective on tumour cell heterogeneity underestimates phenotypic diversity.