Normal tissue architecture determines the evolutionary course of cancer

Jeffrey West (), Ryan O. Schenck, Chandler Gatenbee, Mark Robertson-Tessi and Alexander R. A. Anderson ()
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Jeffrey West: Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute
Ryan O. Schenck: Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute
Chandler Gatenbee: Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute
Mark Robertson-Tessi: Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute
Alexander R. A. Anderson: Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract Cancer growth can be described as a caricature of the renewal process of the tissue of origin, where the tissue architecture has a strong influence on the evolutionary dynamics within the tumor. 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 approach explores a key mechanism behind both inter-patient and intratumoral tumor heterogeneity: competition for space. Time-varying competition leads to an emergent transition from Darwinian premalignant growth to subsequent invasive neutral tumor growth. 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 modulated en route to neutral evolution by the combination of two factors: spatial constraints and limited cellular mixing. These two factors occur naturally in ductal carcinomas, where the branching topology of the ductal network dictates spatial constraints and mixing rates.

Date: 2021
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DOI: 10.1038/s41467-021-22123-1

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