A method for in silico exploration of potential glioblastoma multiforme attractors using single-cell RNA sequencing

Abstract

Abstract We presented a method to find potential cancer attractors using single-cell RNA sequencing (scRNA-seq) data. We tested our method in a Glioblastoma Multiforme (GBM) dataset, an aggressive brain tumor presenting high heterogeneity. Using the cancer attractor concept, we argued that the GBM’s underlying dynamics could partially explain the observed heterogeneity, with the dataset covering a representative region around the attractor. Exploratory data analysis revealed promising GBM’s cellular clusters within a 3-dimensional marker space. We approximated the clusters’ centroid as stable states and each cluster covariance matrix as defining confidence regions. To investigate the presence of attractors inside the confidence regions, we constructed a GBM gene regulatory network, defined a model for the dynamics, and prepared a framework for parameter estimation. An exploration of hyperparameter space allowed us to sample time series intending to simulate myriad variations of the tumor microenvironment. We obtained different densities of stable states across gene expression space and parameters displaying multistability across different clusters. Although we used our methodological approach in studying GBM, we would like to highlight its generality to other types of cancer. Therefore, this report contributes to an advance in the simulation of cancer dynamics and opens avenues to investigate potential therapeutic targets.

Keywords

• Single-cell RNA sequencing
• Glioblastoma multiforme
• Biomarkers
• Cancer attractors
• Confidence regions
• Multistability