Spatial model predicts dispersal and cell turnover cause reduced intra-tumor heterogeneity [article]

Bartlomiej Waclaw, Ivana Bozic, Meredith E Pittman, Ralph H Hruban, Bert Vogelstein, Martin A Nowak
2015 bioRxiv   pre-print
Most cancers in humans are large, measuring centimeters in diameter, 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 their homogeneity - virtually every neoplastic cell within a large cancer contains the same core set of genetic alterations, with heterogeneity confined to mutations that have emerged after the last clonal expansions. How such
more » ... xpansions. How such clones expand within the spatially-constrained three dimensional architecture of a tumor, and come to dominate a large, pre-existing lesion, has never been explained. We here describe a model for tumor evolution that shows how short-range migration and cell turnover can account for rapid cell mixing inside the tumor. With it, we show that even a small selective advantage of a single cell within a large tumor 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 novel insights into spatial and temporal aspects of tumor growth but also suggests that targeting short range cellular migratory activity could have dramatic effects on tumor growth rates.
doi:10.1101/016824 fatcat:qnaamxxuzfeu7e5koq3hwrzkla