Spatial model predicts dispersal and cell turnover cause reduced intra-tumor heterogeneity
Bartlomiej Waclaw , Ivana Bozic , Meredith E Pittman , Ralph H Hruban , Bert Vogelstein , Martin A Nowak
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 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.
BioRXiv: link
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