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

• Published in: Nature (London) 2014-10, Vol.514 (7520), p.54-58
• Main Authors: Marusyk, Andriy, Tabassum, Doris P., Altrock, Philipp M., Almendro, Vanessa, Michor, Franziska, Polyak, Kornelia
• Format: Article
• Language: English
• Subjects: 14; 14/19; 14/32; 631/67/2329; Animals; Apoptosis; Cancer; Cell cycle; Cell Line, Tumor; Cell Proliferation; Clone Cells - metabolism; Clone Cells - pathology; Cloning; Development and progression; Epigenesis, Genetic - genetics; Epigenetics; Female; Heterogeneity; Humanities and Social Sciences; Interleukin-11 - metabolism; Mathematical models; Metastasis; Mice; Models, Biological; Morphology; multidisciplinary; Mutation; Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Phenotype; Science; Tumor Microenvironment; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13556

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. Tumour sub-clone interactions 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.