title: Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity.
abstract: 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.
authors: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Andriy
authors: A
authors: Marusyk
authors: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] BBS Program, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Doris P
authors: DP
authors: Tabassum
authors: 1] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA [3] Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, USA.
authors: Philipp M
authors: PM
authors: Altrock
authors: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Vanessa
authors: V
authors: Almendro
authors: 1] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors: Franziska
authors: F
authors: Michor
authors: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [4] BBS Program, Harvard Medical School, Boston, Massachusetts 02115, USA [5] Harvard Stem Cell Institute and the Broad Institute, Cambridge, Massachusetts 02138, USA.
authors: Kornelia
authors: K
authors: Polyak
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells / Q000378:metabolism* / Q000473:pathology*; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D017370:Interleukin-11 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D059016:Tumor Microenvironment
chemical_list: D017370:Interleukin-11