Abstract
Intratumoral molecular cancer cell heterogeneity is conventionally ascribed to the accumulation of random mutations that occasionally generate fitter phenotypes. This model is built upon the “mutation-selection” paradigm in which mutations drive ever-fitter cancer cells independent of environmental circumstances. An alternative model posits spatio-temporal variation (e.g., blood flow heterogeneity) drives speciation by selecting for cancer cells adapted to each different environment. Here, spatial genetic variation is the consequence rather than the cause of intratumoral evolution. In nature, spatially heterogenous environments are frequently coupled through migration. Drawing from ecological models, we investigate adjacent well-perfused and poorly-perfused tumor regions as “source” and “sink” habitats, respectively. The source habitat has a high carrying capacity resulting in more emigration than immigration. Sink habitats may support a small (“soft-sink”) or no (“hard-sink”) local population. Ecologically, sink habitats can reduce the population size of the source habitat so that, for example, the density of cancer cells directly around blood vessels may be lower than expected. Evolutionarily, sink habitats can exert a selective pressure favoring traits different from those in the source habitat so that, for example, cancer cells adjacent to blood vessels may be suboptimally adapted for that habitat. Soft sinks favor a generalist cancer cell type that moves between the environment but can, under some circumstances, produce speciation events forming source and sink habitat specialists resulting in significant molecular variation in cancer cells separated by small distances. Finally, sink habitats, with limited blood supply, may receive reduced concentrations of systemic drug treatments; and local hypoxia and acidosis may further decrease drug efficacy allowing cells to survive treatment and evolve resistance. In such cases, the sink transforms into the source habitat for resistant cancer cells, leading to treatment failure and tumor progression. We note these dynamics will result in spatial variations in molecular properties as an alternative to the conventional branched evolution model and will result in cellular migration as well as variation in cancer cell phenotype and proliferation currently described by the stem cell paradigm.
Highlights
Regional variations in the molecular properties of cancer cells have been well established and are usually ascribed to accumulation of genetic changes, often called branched evolution, as each mutation initiates a new species (Fisher et al, 2012; Gerlinger et al, 2012; Zhang et al, 2019)
We propose source-sink dynamics contribute to the spatial variability in molecular properties of cancer cells observed within and between tumors in the same patient
We demonstrate how source-sink dynamics are applicable to cancers and can produce the observed spatial variations in genetic and phenotypic properties of cancer cells, and suggest critical issues in designing patient treatment strategies
Summary
Regional variations in the molecular properties of cancer cells have been well established and are usually ascribed to accumulation of genetic changes, often called branched evolution, as each mutation initiates a new species (Fisher et al, 2012; Gerlinger et al, 2012; Zhang et al, 2019). Though most mutations are deleterious, the rare mutation that increases fitness will allow increased proliferation producing a genetically distinct subpopulation and, observable regional genotypic variations This paradigm (Archetti, 2013; Scott and Marusyk, 2017; Hinohara and Polyak, 2019) tends to neglect the role of spatio-temporal heterogeneity in environmental selection forces as a driver of evolution. Natural selection may favor genetically and molecularly distinct cancer cells phenotypically suited to the local habitat type These local habitat-specific cancer cell populations are not completely isolated. We explore migration as a previously unrecognized driver of intra-tumoral evolution (Winker, 2000)
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