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Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity

2014; Nature Portfolio; Volume: 514; Issue: 7520 Linguagem: Inglês

10.1038/nature13556

1476-4687

Andriy Marusyk, Doris P. Tabassum, Philipp M. Altrock, Vanessa Almendro, Franziska Michor, Kornélia Polyák,

Microtubule and mitosis dynamics

Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumours. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumour phenotypes and the competitive expansion of individual clones. We found that tumour growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumour by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumour collapse. We developed a mathematical modelling framework to identify the rules underlying the generation of intra-tumour clonal heterogeneity. We found that non-cell-autonomous driving of tumour growth, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits. To investigate the role of sub-clonal tumour heterogeneity in cancer progression, a mouse xenograft model was used which revealed that tumour growth can be driven by a minor cell subpopulation by a non-cell-autonomous mechanism, although this minor subpopulation can be outcompeted by faster proliferating competitors. Tumours are often composed of cell populations that differ in their genetic lesions and biological properties, but how such 'sub-clonal' heterogeneity arises and with what consequences on cancer progression is still relatively obscure. Now Kornelia Polyak and colleagues have used a mouse model to show that tumour growth can be driven by a minor cell subpopulation through a non-cell-autonomous mechanism. This minor subpopulation can, however, also be outcompeted by faster proliferating competitors, resulting in tumour collapse. The results illustrate the complexity of sub-clone interactions and clonal interference in heterogeneous tumours, with potential implications for therapy.