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Cancer cells exhibit clonal diversity in phenotypic plasticity.

ABSTRACT: Phenotypic heterogeneity in cancers is associated with invasive progression and drug resistance. This heterogeneity arises in part from the ability of cancer cells to switch between phenotypic states, but the dynamics of this cellular plasticity remain poorly understood. Here we apply DNA barcodes to quantify and track phenotypic plasticity across hundreds of clones in a population of cancer cells exhibiting epithelial or mesenchymal differentiation phenotypes. We find that the epithelial-to-mesenchymal cell ratio is highly variable across the different clones in cancer cell populations, but remains stable for many generations within the progeny of any single clone-with a heritability of 0.89. To estimate the effects of combination therapies on phenotypically heterogeneous tumours, we generated quantitative simulations incorporating empirical data from our barcoding experiments. These analyses indicated that combination therapies which alternate between epithelial- and mesenchymal-specific treatments eventually select for clones with increased phenotypic plasticity. However, this selection could be minimized by increasing the frequency of alternation between treatments, identifying designs that may minimize selection for increased phenotypic plasticity. These findings establish new insights into phenotypic plasticity in cancer, and suggest design principles for optimizing the effectiveness of combination therapies for phenotypically heterogeneous tumours.

SUBMITTER: Mathis RA

PROVIDER: S-EPMC5356442 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Cancer cells exhibit clonal diversity in phenotypic plasticity.

Mathis Robert Austin RA Sokol Ethan S ES Gupta Piyush B PB

Open biology 20170201 2

Phenotypic heterogeneity in cancers is associated with invasive progression and drug resistance. This heterogeneity arises in part from the ability of cancer cells to switch between phenotypic states, but the dynamics of this cellular plasticity remain poorly understood. Here we apply DNA barcodes to quantify and track phenotypic plasticity across hundreds of clones in a population of cancer cells exhibiting epithelial or mesenchymal differentiation phenotypes. We find that the epithelial-to-mes ...[more]

PMID: 28202626

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Project description:BackgroundClonal marine organisms exhibit high levels of morphological variation. Morphological differences may be a response to environmental factors but also they can be attributed to accumulated genetic differences due to disruption of gene flow among populations. In this study, we examined the extensive morphological variation (of 14 characters) in natural populations observed in the gorgonian Eunicea flexuosa, a widely distributed Caribbean octocoral. Eco-phenotypic and genetic effects were evaluated by reciprocal transplants of colonies inhabiting opposite ends of the depth gradient and analysis of population genetics of mitochondrial and nuclear genes, respectively.ResultsSignificant differences (P < 0.001) in 14 morphological traits were found among colonies inhabiting 12 locations distributed in seven reefs in southwest Puerto Rico. Results from principal component analysis indicated the presence of two groups based on depth distribution, suggesting the presence of two discrete morphotypes (i.e. shallow type < 5 m and deep type > 17 m). A discriminant function analysis based on a priori univariate and multivariate analyses (which separated the colonies in morphotypes) correctly classified 93% of the colonies for each environment. Light, water motion and sediment transport might influence the distribution of the two morphotypes. Reaction norms of morphological characters of colonies reciprocally transplanted showed gradual significant changes through the 15 months of transplantation. Sclerites of shallow water colonies became larger when transplanted to deeper environments and vice versa, but neither of the two transplanted groups overlapped with the residents' morphology. Genetic analysis of mitochondrial and nuclear genes suggested that such discrete morphology and non-overlapping phenotypic plasticity is correlated with the presence of two independent evolutionary lineages. The distribution of the lineages is non-random and may be related to adaptational responses of each lineage to the environmental demands of each habitat.ConclusionThe extensive distribution and ample morphological variation of Eunicea flexuosa corresponds to two distinct genetic lineages with narrower distributions and more rigid phenotypic plasticity than the original description. The accepted description sensu Bayer (1961) of E. flexuosa is a complex of at least two distinct genetic lineages, adapted to different habitats and do not exchange genetic material despite living in sympatry. The present study highlights the importance of correctly defining species, because the unknowingly use of species complexes can overestimate geographical distribution, population abundance, and physiological tolerance.

Project description:The burgeoning cannabis market requires evidence-based science such that farmers can quickly and efficiently generate new plants. In part, horticultural operations are limited by the success of cloning procedures. Here, we measured the role of environmental conditions and cultivar identity on the success of generating long branch material with many meristems in planting stock (mothers) and in rooting success of stem-derived clones. To evaluate the influence of lighting treatments on the optimal production of branching mothers, four lighting conditions (Fluorescent High Output T5s [T5], Metal halide lamps [MH], Plasma lamps [PL], or Metal halide lamps augmented with far red LED lights [MH+FR]) were applied to two cultivars of container grown plants (Cannabis sativa L. 'Bubba Kush', 'Ghost Train Haze') grown in peat-based organic substrates in mylar grow tents. To evaluate the influence of lighting, cutting tool (secateurs or scalpels), and stem wounding (present/absent) on optimal rooting of stems, three lighting conditions (Fluorescent T8s, T5, PL) were applied to three cultivars of peat pellet grown plants (C. sativa L. 'Bubba Kush', 'Ghost Train Haze', 'Headband'). Mothers grown under T5 and MH (vs MH+FR) produced ~30% more meristems. However, growing mothers under MH+FR were 19% taller than mothers under T5, with ~25% longer internodes on dominant stems than plants under any other lighting condition. Canopies were denser under T5 because petiole length was ~30% shorter under T5 and fan leaves were longer and narrower under MH+FR and MH+FR and PL, respectively, than under other lighting conditions. Cultivar Ghost Train Haze stems rooted most frequently and most quickly. Wounded stems were 162% more likely to root than unwounded stems and rooted 1.5 days earlier. Our results will guide producers attempting to maximize the rate of clone production in licensed facilities; although results may differ among cultivars, where cultivars differed in their average phenotype as mother plants, and their propensity to root from cuttings, and the speed with which they produced those roots.

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Cancer cells exhibit clonal diversity in phenotypic plasticity.

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Cancer cells exhibit clonal diversity in phenotypic plasticity.

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