Clonal evolution is the driving force behind many current public health issues such as cancer and infectious disease. However, limited efforts have been invested in treating and preventing these conditions from an evolutionary perspective. Critically, the ability to forecast tumor evolution depends on the relative contribution of deterministic and stochastic processes. Although direct observations of human tumor evolution are impractical, patterns of somatic alterations amongst cells within a tumor faithfully report on their past proliferative history. Unexpectedly, we recently found that after transformation, some tumors grow in the absence of stringent selection, compatible with effectively neutral evolution. This led to our description of a novel Big Bang model of tumor growth where the tumor grows as a single terminal expansion populated by numerous heterogeneous?and effectively equally fit subclones. This new model contrasts with the de facto sequential clonal expansion model, and suggests that tumor-initiating events are both necessary and sufficient to propagate subsequent growth. Moreover, these findings raise the tantalizing possibility that the earliest events during tumor growth shape its subsequent evolutionary trajectory. Here we rigorously test the novel hypothesis that early tumor evolution is deterministic and seek to define its contingencies. We thus perform oncogene-engineering and cellular barcoding of wild-type human organoids to characterize clonal dynamics and the functional determinants of increased fitness during in vitro tumor evolution. This innovative lineage tracing strategy enables the direct measurement of evolutionary parameters in human cells, while rendering a comprehensive genotype to phenotype map during tumor progression. In parallel, we will infer the timing of metastatic dissemination and evaluate whether the metastatic phenotype is specified early through computational and mathematical modeling of patient genomic data. This systems biology approach will evaluate the predictability of tumor evolution towards the development of models to forecast disease progression and guide earlier detection, thereby reducing cancer related mortality. ! !
Clonal evolution is the driving force behind many current public health issues such as cancer and infectious disease, but limited efforts have been invested in treating and preventing these conditions from an evolutionary perspective. Here we test whether the earliest stages of tumor progression are predictable by ?engineering? mutations in normal human 3-D organoid culture, coupled with lineage tracing, and computational modeling. This integrative experimental and computational approach will inform predictive models to enable earlier detection and durable disease control, thereby reducing cancer related mortality. !
