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Exploring Notch Pathway to Elucidate Phenotypic Plasticity and Intra-tumor Heterogeneity in Gliomas.

ABSTRACT: The phenotypic plasticity and self-renewal of adult neural (aNSCs) and glioblastoma stem cells (GSCs) are both known to be governed by active Notch pathway. During development, GSCs can establish differential hierarchy to produce heterogeneous groups of tumor cells belong to different grades, which makes the tumor ecosystem more complex. However, the molecular events regulating these entire processes are unknown hitherto. In this work, based on the mechanistic regulations of Notch pathway activities, a novel computational framework is introduced to inspect the intra-cellular reactions behind the development of normal and tumorigenic cells from aNSCs and GSCs, respectively. The developmental dynamics of aNSCs/GSCs are successfully simulated and molecular activities regulating the phenotypic plasticity and self-renewal processes in normal and tumor cells are identified. A novel scoring parameter "Activity Ratio" score is introduced to find out driver molecules responsible for the phenotypic plasticity and development of different grades of tumor. A new quantitative method is also developed to predict the future risk of Glioblastoma tumor of an individual with appropriate grade by using the transcriptomics profile of that individual as input. Also, a novel technique is introduced to screen and rank the potential drug-targets for suppressing the growth and differentiation of tumor cells.

SUBMITTER: Chowdhury S

PROVIDER: S-EPMC6602950 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Colorectal cancer arises in part from the cumulative effects of multiple gene lesions. Recent studies in selected cancer types have revealed significant intra-tumor genetic heterogeneity and highlighted its potential role in disease progression and resistance to therapy. We hypothesized the existence of significant intra-tumor genetic heterogeneity in rectal cancers involving variations in localized somatic mutations and copy number abnormalities. Two or three spatially disparate regions from each of six rectal tumors were dissected and subjected to the next-generation whole-exome DNA sequencing, Oncoscan SNP arrays, and targeted confirmatory sequencing and analysis. The resulting data were integrated to define subclones using SciClone. Mutant-allele tumor heterogeneity (MATH) scores, mutant allele frequency correlation, and mutation percent concordance were calculated, and copy number analysis including measurement of correlation between samples was performed. Somatic mutations profiles in individual cancers were similar to prior studies, with some variants found in previously reported significantly mutated genes and many patient-specific mutations in each tumor. Significant intra-tumor heterogeneity was identified in the spatially disparate regions of individual cancers. All tumors had some heterogeneity but the degree of heterogeneity was quite variable in the samples studied. We found that 67-97% of exonic somatic mutations were shared among all regions of an individual's tumor. The SciClone computational method identified 2-8 shared and unshared subclones in the spatially disparate areas in each tumor. MATH scores ranged from 7 to 41. Allele frequency correlation scores ranged from R(2)=0.69-0.96. Measurements of correlation between samples for copy number changes varied from R(2)=0.74-0.93. All tumors had some heterogeneity, but the degree was highly variable in the samples studied. The occurrence of significant intra-tumor heterogeneity may allow selected tumors to have a genetic reservoir to draw from in their evolutionary response to therapy and other challenges.

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Exploring Notch Pathway to Elucidate Phenotypic Plasticity and Intra-tumor Heterogeneity in Gliomas.

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