Single cell spatial analysis identifies regulators of brain tumor initiating cells

Abstract

Glioblastomas (GBMs) are aggressive brain tumors with extensive intratumoral heterogeneity. Here, we used spatial transcriptomics and single-cell ATAC-seq to dissect the transcriptome of distinct anatomical regions of the tumor microenvironment. We identified numerous extracellular matrix (ECM) molecules including biglycan elevated in areas infiltrated with brain tumor-initiating cells (BTICs). Single-cell RNA sequencing showed that the ECM molecules were differentially expressed by cells including injury response versus developmental BTICs. Exogeneous biglycan or overexpression of biglycan resulted in a higher proliferation rate of BTICs, and this was associated mechanistically with LDL receptor-related protein 6 (LRP6) binding and activation of the Wnt/{beta}-catenin pathway. Biglycan-overexpressing BTICs grew to a larger tumor mass when implanted intracranially in mice. This study points to the spatial heterogeneity of ECM molecules in the GBM microenvironment and suggests biglycan-LRP6 axis as a therapeutic target to curb GBM growth.