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Tissue structure accelerates evolution: premalignant sweeps precede neutral expansion

View ORCID ProfileJeffrey West, View ORCID ProfileRyan Schenck, View ORCID ProfileChandler Gatenbee, View ORCID ProfileMark Robertson-Tessi, View ORCID ProfileAlexander RA Anderson
doi: https://doi.org/10.1101/542019
Jeffrey West
H. Lee Moffitt Cancer Center & Research Institute;
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Ryan Schenck
University of Oxford
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Chandler Gatenbee
H. Lee Moffitt Cancer Center & Research Institute;
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Mark Robertson-Tessi
H. Lee Moffitt Cancer Center & Research Institute;
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Alexander RA Anderson
H. Lee Moffitt Cancer Center & Research Institute;
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  • For correspondence: alexander.ra.anderson@gmail.com
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Abstract

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 growth. 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 progenitors. So-called "born to be bad" tumors arise from progenitors which may already possess the necessary driver mutations for malignancy and metastasis. 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 tempo. Using a classic, well-studied model of tumor evolution (a passenger-driver mutation model) 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 (neutral to Darwinian) without a change in cell-specific mutation rate or fitness effects. Transition from early Darwinian to late neutral evolution is accelerated by the combination of two factors: spatial constraints and well-timed dispersal events.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 10, 2019.
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Tissue structure accelerates evolution: premalignant sweeps precede neutral expansion
Jeffrey West, Ryan Schenck, Chandler Gatenbee, Mark Robertson-Tessi, Alexander RA Anderson
bioRxiv 542019; doi: https://doi.org/10.1101/542019
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Tissue structure accelerates evolution: premalignant sweeps precede neutral expansion
Jeffrey West, Ryan Schenck, Chandler Gatenbee, Mark Robertson-Tessi, Alexander RA Anderson
bioRxiv 542019; doi: https://doi.org/10.1101/542019

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