Fuzzy Unheritance: A Novel Form Of Somatic Cell Inheritance That Regulates Cell Population Heterogeneity

Multi-level heterogeneity is a characteristic feature of cancer cell populations. However, how a cell population regulates and maintains its cell population heterogeneity is not well understood. Based on conventional theories of genetic inheritance, cell division is precise, where a daughter cell inherits an identical karyotype from its mother cell. Therefore, errors that are generated during cell division occur at low frequencies that take prolonged time periods to accumulate. However, the overwhelming heterogeneity found in unstable cancers is largely inconsistent with current models of genetic inheritance. In order to determine the mechanism of how heterogeneity is regulated, the pattern of inherited traits, including karyotype and growth rate, are compared in cell lines with different degrees of genome instability. Single cell and population-based assays were conducted and illustrate the following: 1) single unstable cells cannot pass a specific karyotype or growth rate and instead pass a heterogeneous array of karyotypes and growth rates; 2) genome heterogeneity is linked to other heterogeneous features of the system, like growth heterogeneity; 3) cells that are outliers dominate cell population dynamics when the cell population is unstable; and 4) the statistical average does not give an accurate portrayal of unstable cell populations. Altogether, this suggests that genome instability leads to genome replacement-mediated macro-cellular evolution that precludes the clonal expansion of a few abnormal cells; and 2) a given degree of heterogeneity can be inherited from a single cell. Because a given degree of heterogeneity is inherited, and the specific variants change between cell passages, this inheritance is termed fuzzy inheritance. According to fuzzy inheritance, rather than passing specific changes, the potential to generate genomic variation is passed. Fuzzy inheritance provides a cell population with the necessary evolvability and explains how heterogeneity is regulated and maintained in normal tissue and in cancer cells

Cancer evolution: Darwin and beyond

Clinical and laboratory studies over recent decades have established branched evolution as a feature of cancer. However, while grounded in somatic selection, several lines of evidence suggest a Darwinian model alone is insufficient to fully explain cancer evolution. First, the role of macroevolutionary events in tumour initiation and progression contradicts Darwin's central thesis of gradualism. Whole-genome doubling, chromosomal chromoplexy and chromothripsis represent examples of single catastrophic events which can drive tumour evolution. Second, neutral evolution can play a role in some tumours, indicating that selection is not always driving evolution. Third, increasing appreciation of the role of the ageing soma has led to recent generalised theories of age-dependent carcinogenesis. Here, we review these concepts and others, which collectively argue for a model of cancer evolution which extends beyond Darwin. We also highlight clinical opportunities which can be grasped through targeting cancer vulnerabilities arising from non-Darwinian patterns of evolution

Investigating evolutionary hypotheses of cancer cell motility

Cancer is a disease of evolution. Mutations within a cell lead to the acquisition of cancerous phenotypes. Tumour evolution depends on heritable differences between cells. The extent of heritable variation has not been measured for any trait in cancer cellpopulations. In this thesis techniques have been developed to estimate the broad-sense heritability (H2) of cancer cell traits in vitroand usedto estimate the H2of cell motility. Cell motility is a trait related to the cancer hallmark of metastasis. Results showthat motility is strongly heritable with H2values ranging from 0.77-0.36 across multiple cell generations. H2estimates appeared to decrease slightly between more distantly related cells, a trend that could occur due to a decrease in the genetic contribution to motility or an increase in environmental variation. This was tested by treating cells with epigenetic inhibitors and obtaining H2 estimates.Results showed H2estimates were not significantly affected by the application of epigenetic inhibitorswith values ranging from 0.95-0.18.Quantification of the amount of environmental variation in in vitrocell culture media was attempted using image analysis of fluorescent particles. Variation in particle distribution was found at a range of concentrations, nM –mM. Direct quantitative measures of evolvability in cell traits could have valuable applications to cancer research and tumour treatment.To understand tumour progression, evolutionary theory can be applied to cancer cells in vitroto elucidate the selective pressures driving the evolution of cancer cell traits. In this project experimental evolution techniques have been adapted from microbiology and applied to cancer cell linesin vitro. Adaptation of cell lines to lownutrient environments over 12 weeks showed dispersal theory may play a role in the selection of the cancer cell trait motility. Understanding the selective pressures driving the acquisition of cancer phenotypes will have valuable applications clinically inunderstandingtumour progression

A single dividing cell population with imbalanced fate drives oesophageal tumour growth.

Understanding the cellular mechanisms of tumour growth is key for designing rational anticancer treatment. Here we used genetic lineage tracing to quantify cell behaviour during neoplastic transformation in a model of oesophageal carcinogenesis. We found that cell behaviour was convergent across premalignant tumours, which contained a single proliferating cell population. The rate of cell division was not significantly different in the lesions and the surrounding epithelium. However, dividing tumour cells had a uniform, small bias in cell fate so that, on average, slightly more dividing than non-dividing daughter cells were generated at each round of cell division. In invasive cancers induced by Kras(G12D) expression, dividing cell fate became more strongly biased towards producing dividing over non-dividing cells in a subset of clones. These observations argue that agents that restore the balance of cell fate may prove effective in checking tumour growth, whereas those targeting cycling cells may show little selectivity.Cancer Research UK (Grant ID: C609/A17257), Medical Research Council (Grant-in-Aid), DFG (Research Fellowship), Engineering and Physical Sciences Research Council (Critical Mass Grant), Wellcome Trust (Grant ID: 098357/Z/12/Z)This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ncb340