Cooperation of partially-transformed clones: an invisible force behind the early stages of carcinogenesis

Abstract

Running title: Oncogenic field effect and clonal heterogeneity AbstractMost tumours exhibit significant heterogeneity and are best described as communities of cellular populations competing for resources. Growing experimental evidence also suggests, however, that cooperation between cancer clones is important as well for the maintenance of tumour heterogeneity and tumour progression. However, a role for cell communication during the earliest steps in oncogenesis is not well characterised despite its vital importance in normal tissue and clinically manifest tumours. By modelling the interaction between the mutational process and cell-to-cell communication in three-dimensional tissue architecture, we show that non-cell-autonomous mechanisms of carcinogenesis are likely to support and accelerate precancerous clonal expansion through the cooperation of different, non-or partially-transformed mutants. We predict the existence of a 'cell-autonomous time-horizon', a time before which cooperation between cell-to-cell communication and DNA mutations might be one of the most fundamental forces shaping the early stages of oncogenesis. The understanding of this process could shed new light on the mechanisms leading to clinically manifest cancers.However, it is unclear if these observations, often obtained using model systems with carcinogens or established tumour clones, can be recapitulated at the low mutational rates occurring naturally 10 . Furthermore, it is unknown at which stage of carcinogenesis, non-cellautonomous mechanisms might have a role 9 . As cell-to-cell communication and clonal interaction are often neglected in formal models of carcinogenesis, we propose a model for the interaction between the mutagenic process and cell-to-cell communication within a threedimensional tissue architecture. We developed the simplest possible models to capture the basic emergent properties of early oncogenesis in the presence of mutations and clonal cellto-cell communication. We propose that the extremely low mutational frequency encountered in physiological conditions does not render cooperation between mutations in adjacent cells unlikely butrather the oppositethat synergy between the mutational process and cell-tocell communication might play a fundamental role in carcinogenesis.