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Tissue structure accelerates evolution: premalignant sweeps precede neutral expansion

View ORCID ProfileJeffrey West, View ORCID ProfileRyan O. Schenck, View ORCID ProfileChandler Gatenbee, View ORCID ProfileMark Robertson-Tessi, View ORCID ProfileAlexander R. A. Anderson
doi: https://doi.org/10.1101/542019
Jeffrey West
1Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, SRB 4 Rm 24000H Tampa, Florida, 33612
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Ryan O. Schenck
1Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, SRB 4 Rm 24000H Tampa, Florida, 33612
2Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX37BN, UK
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Chandler Gatenbee
1Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, SRB 4 Rm 24000H Tampa, Florida, 33612
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Mark Robertson-Tessi
1Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, SRB 4 Rm 24000H Tampa, Florida, 33612
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Alexander R. A. Anderson
1Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, SRB 4 Rm 24000H Tampa, Florida, 33612
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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 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 (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 O. Schenck, Chandler Gatenbee, Mark Robertson-Tessi, Alexander R. A. 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 O. Schenck, Chandler Gatenbee, Mark Robertson-Tessi, Alexander R. A. Anderson
bioRxiv 542019; doi: https://doi.org/10.1101/542019

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