title: A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity.
abstract: Most cancers in humans are large, measuring centimetres in diameter, and composed of many billions of cells. An equivalent mass of normal cells would be highly heterogeneous as a result of the mutations that occur during each cell division. What is remarkable about cancers is that virtually every neoplastic cell within a large tumour often contains the same core set of genetic alterations, with heterogeneity confined to mutations that emerge late during tumour growth. How such alterations expand within the spatially constrained three-dimensional architecture of a tumour, and come to dominate a large, pre-existing lesion, has been unclear. Here we describe a model for tumour evolution that shows how short-range dispersal and cell turnover can account for rapid cell mixing inside the tumour. We show that even a small selective advantage of a single cell within a large tumour allows the descendants of that cell to replace the precursor mass in a clinically relevant time frame. We also demonstrate that the same mechanisms can be responsible for the rapid onset of resistance to chemotherapy. Our model not only provides insights into spatial and temporal aspects of tumour growth, but also suggests that targeting short-range cellular migratory activity could have marked effects on tumour growth rates.
authors: School of Physics and Astronomy, University of Edinburgh, JCMB, Peter Guthrie Tait Road, Edinburgh EH9 3FD, UK.
authors: Bartlomiej
authors: B
authors: Waclaw
authors: Program for Evolutionary Dynamics, Harvard University, One Brattle Square, Cambridge, Massachusetts 02138, USA.|Department of Mathematics, Harvard University, One Oxford Street, Cambridge, Massachusetts 02138, USA.
authors: Ivana
authors: I
authors: Bozic
authors: The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, 401 North Broadway, Weinberg 2242, Baltimore, Maryland 21231, USA.
authors: Meredith E
authors: ME
authors: Pittman
authors: The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, 401 North Broadway, Weinberg 2242, Baltimore, Maryland 21231, USA.
authors: Ralph H
authors: RH
authors: Hruban
authors: The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, 401 North Broadway, Weinberg 2242, Baltimore, Maryland 21231, USA.|Ludwig Center and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, 1650 Orleans Street, Baltimore, Maryland 21287, USA.
authors: Bert
authors: B
authors: Vogelstein
authors: Program for Evolutionary Dynamics, Harvard University, One Brattle Square, Cambridge, Massachusetts 02138, USA.|Department of Mathematics, Harvard University, One Oxford Street, Cambridge, Massachusetts 02138, USA.|Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge, Massachusetts 02138, USA.
authors: Martin A
authors: MA
authors: Nowak
mesh_terms: D002455:Cell Division; D002465:Cell Movement; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D019143:Evolution, Molecular; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012641:Selection, Genetic; D013997:Time Factors