LETTER doE10.1038/nature14971 A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity Bartlomiej WaclawI, Ivana Bozic 13, Meredith E. Pittman'', Ralph H. Hruban4, Bert Vogelstein“ & Martin A. NowaIc2-1.6 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 remark- able about cancers is that virtually every neoplastic cell within a large tumour often contains the same core set of genetic altera- tions, 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 median- isms can be responsible for the rapid onset of resistance to chemo- therapy. Our model not only provides insights into spatial and temporal aspects of tumour growth, but also suggests that target- ing short-range cellular migratory activity could have marked effects on tumour growth rates. Tumour growth is initiated when a single cell acquires genetic or epigenetic alterations that change the net growth rate of the cell (birth minus death), and enable its progeny to outgrow surrounding cells. As these small lesions grow, the cells acquire additional alterations that cause them to multiply even faster and to change their metabolism to survive better the harsh conditions and nutrient depriva