PT  - JOURNAL ARTICLE
AU  - Jeffrey West
AU  - Ryan O. Schenck
AU  - Chandler Gatenbee
AU  - Mark Robertson-Tessi
AU  - Alexander R. A. Anderson
TI  - Tissue structure accelerates evolution: premalignant sweeps precede neutral expansion
AID  - 10.1101/542019
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 542019
4099  - http://biorxiv.org/content/early/2019/07/11/542019.short
4100  - http://biorxiv.org/content/early/2019/07/11/542019.full
AB  - Cancer has been hypothesized to be a caricature of the renewal process of the tissue of origin: arising from (and maintained by) small subpopulations capable of continuous growth1. The strong influence of the tissue structure has been convincingly demonstrated in intestinal cancers where adenomas grow by the fission of stem-cell-maintained glands influenced by early expression of abnormal cell mobility in cancer progenitors2, 3. So-called “born to be bad” tumors arise from progenitors which may already possess the necessary driver mutations for malignancy4, 5 and metastasis6. These tumors subsequently evolve neutrally, thereby maximizing intratumoral heterogeneity and increasing the probability of therapeutic resistance. These findings have been nuanced by the advent of multi-region sequencing, which uses spatial and temporal patterns of genetic variation among competing tumor cell populations to shed light on the mode of tumor evolution (neutral or Darwinian) and also the tempo4, 7–11. Using a classic, well-studied model of tumor evolution (a passenger-driver mutation model12–16) we systematically alter spatial constraints and cell mixing rates to show how tissue structure influences functional (driver) mutations and genetic heterogeneity over time. This model approach explores a key mechanism behind both inter-patient and intratumoral tumor heterogeneity: competition for space. Initial spatial constraints determine the emergent mode of evolution (Darwinian to neutral) without a change in cell-specific mutation rate or fitness effects. Driver acquisition during the Darwinian precancerous stage may be accelerated en route to neutral evolution by the combination of two factors: spatial constraints and limited cellular mixing.