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

Saikat Chowdhury,Ram Rup Sarkar

doi:10.1038/s41598-019-45892-8

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.

Highlights

Notch signaling pathway, which is commonly known for the maintenance and proliferation of the adult neural stem cells in the neurogenic niche of SVZ, is implicated in the proliferation of GSCs1
Quiescent cells were significantly reduced, and simultaneously the differentiated NPC cells were increased. These results proved that the transcriptomics profile of The Cancer Genome Atlas (TCGA)-glioblastoma development (GBM) tumor samples cohort could trigger stem cell differentiation as well as tumorigenesis
The molecular signatures between adult NSCs and tumorigenic glioblastoma stem cells (GSCs) are observed to be similar in various aspects, and it is understood that both of these cells share a common origin of evolution during development[3]

Summary

Introduction

Notch signaling pathway, which is commonly known for the maintenance and proliferation of the adult neural stem cells (aNSCs) in the neurogenic niche of SVZ, is implicated in the proliferation of GSCs1. The underlying molecular processes of Notch and its cross-talks pathways are attempted to be explored by using computational modeling approach, which in turn helps to assess the governing principles working behind the self-renewal, differentiation, apoptosis, and cell growth arrest (i.e., quiescent state) of aNSCs/ GSCs or GBM tumor cells. By assessing the variances in the expressions/activities of the genes/proteins considered in the individual tumor cells, this work is competent to dissect the underlying mechanisms working behind the emergence of different sub-types and heterogeneous populations of GBM tumor cells Based on these basic understandings, these models are further implicated to perform futuristic predictions of the transformation of low-grade astrocytoma to high-grade GBM, and the chances of occurrences of heterogeneous populations of GSCs and matured GBM cells in the GBM ecosystem. Is there any role played by Notch pathway during apoptosis and cell growth arrest (or quiescent state) of aNSCs/GSCs? Does P53 mutation hinder the neurogenesis or other cellular differentiation of GSCs? What are the main component proteins of Notch pathway, which form the regulatory switch to regulate the differentiation of different cell lineages from aNSCs/GSCs?

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