Abstract
Recent cancer research has investigated the possibility that non-cell-autonomous (NCA) driving tumor growth can support clonal diversity (CD). Indeed, mutations can affect the phenotypes not only of their carriers (“cell-autonomous”, CA effects), but also sometimes of other cells (NCA effects). However, models that have investigated this phenomenon have only considered a restricted number of clones. Here, we designed an individual-based model of tumor evolution, where clones grow and mutate to yield new clones, among which a given frequency have NCA effects on other clones’ growth. Unlike previously observed for smaller assemblages, most of our simulations yield lower CD with high frequency of mutations with NCA effects. Owing to NCA effects increasing competition in the tumor, clones being already dominant are more likely to stay dominant, and emergent clones not to thrive. These results may help personalized medicine to predict intratumor heterogeneity across different cancer types for which frequency of NCA effects could be quantified.
Highlights
Patient biopsies reveal that most of solid tumors display a high diversity of cancer cell subtypes[1]
Mutations with NCA effects could exaggerate the differences in growth kinetics already existing between clones: detrimental mutations with NCA effects could limit the probability for emerging clones to reach high frequencies, and beneficial mutations with NCA effects could accelerate the growth kinetics of already fast growing clones
Tumors growing until a fixed size could evolve during a wider timeframe (88 to 1492 generations) than tumors growing during a fixed number of generations (300 generations): this configuration could render the positive relationship between Clonal diversity (CD) and NCA effects risky to interpret
Summary
Patient biopsies reveal that most of solid tumors display a high diversity of cancer cell subtypes[1]. NCA effects of mutations were found to directly impact the growth of noncarrier clones by many different mechanisms (Supporting information, Table S1)[23] This body of NCA effects is already taken into account in the design of patient-derived models of tumors to yield similar ITH in vitro as in vivo[22], but in silico models of CD evolution have very poorly addressed the impacts of NCA effects so far. Mutations with NCA effects could balance the growth kinetics of the diversity of preexisting clones in the tumor: beneficial mutations with NCA effects could allow slow growing clones (potentially carrying detrimental mutations) to persist, and detrimental mutations with NCA effects could mitigate the outgrowth of fast growing clones This would allow the coexistence of clones at similar frequencies, and support CD. In order to disentangle the link between NCA-driven growth kinetics and CD, we simulated tumors growing either during a fixed number of generations, or until they reached a fixed size, whereas CA and NCA effects had various impacts on clonal growth kinetics
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