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

Data accessibility: All the code and data used in this paper are available at the GitHub repository alesposito/CloE-PE (https://doi.org/10.5281/zenodo.4410222).Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c. 5289077.Copyright 2021. Most tumours exhibit significant heterogeneity and are best described as communities of cellular populations competing for resources. Growing experimental evidence also suggests 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 characterized despite its vital importance in normal tissue and clinically manifest tumours. Here, we present a simple analytical model and stochastic lattice-based simulations to study how the interaction between the mutational process and cell-to-cell communication in three-dimensional tissue architecture might contribute to shape early oncogenesis. We show that non-cell-autonomous mechanisms of carcinogenesis could support and accelerate pre-cancerous 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.CRUK with a multi-disciplinary project award (OncoLive, C54674/A27487); pump-priming funds from the CRUK Cambridge Center (C9685/A25117, C9685/A28397); Medical Research Council program grants (MC_UU_12022/1 and MC_UU_12022/8)